Chiral Indole Compounds and Their Use

ABSTRACT

The present disclosure relates to indole compounds and pharmaceutical compositions thereof, and their use in stimulating the immune system of patients in need thereof and in treating cancer.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a division of U.S. application Ser. No. 17/179,323,filed Feb. 18, 2021, which is a continuation of InternationalApplication PCT/US2020/028371, filed Apr. 15, 2020, which claimspriority from U.S. Provisional Application 62/834,140, filed Apr. 15,2019, and U.S. Provisional Application 62/861,123, filed Jun. 13, 2019.The disclosures of the aforementioned priority applications areincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present disclosure relates to chiral indole compounds and their usein treating patients in need thereof, such as patients with cancer or inneed of immune stimulation.

BACKGROUND OF THE INVENTION

The aryl hydrocarbon (Ah) receptor (AhR) is a ligand-inducibletranscription factor and a member of the basichelix-loop-helix/Per-Arnt-Sim (bHLH/PAS) superfamily. Upon binding toits ligand, AhR mediates a series of biological processes, includingcell division, apoptosis, 20 cell differentiation, adiposedifferentiation, hypothalamus actions, angiogenesis, immune systemmodulation, teratogenicity, tumorigenicity, tumor progression,chloracne, wasting, actions of hormonal systems (e.g., estrogen andandrogen), and expression of genes of the P450 family (Poland et al.,Annu. Rev. Pharmacol. Toxicol. 22:517-554 (1982); Poellinger et al.,Food Addit Contam. 17(4):261-6 (2000); Bock et al., Biochem. Pharmacol.69(10):1403-1408 (2005); 25 Stevens et al., Immunology 127(3):299-311(2009); Puga et al., Biochem Pharmacol. 69(2):199-207 (2005); Safe etal., Int J Oncol. 20(6):1123-8 (2002); Dietrich et al., Carcinogenesis31(8):1319-1328 (2010); U.S. Pat. No. 7,419,992). The liganded receptorparticipates in biological processes through translocation fromcytoplasm into the nucleus, heterodimerization with another factor namedAh receptor nuclear translocator, and binding of the heterodimer to the30 Ah response element of AhR-regulated genes, resulting in enhancementor inhibition of transcription of those genes.

The AhR is able to bind, with different affinities, to several groups ofexogenous chemicals, or artificial ligands, including polycyclicaromatic hydrocarbons, e.g., 3-methylchoranthrene (3-MC), andhalogenated aromatic hydrocarbons, e.g.,2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Studies with those AhRartificial ligands have helped in advancing the understanding of the AhRsystem. An endogenous or physiological ligand for the AhR has beenidentified as 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acidmethyl ester (ITE), with the following structure:

SUMMARY OF THE INVENTION

The present disclosure provides indole compounds useful in modulating anactivity of human aryl hydrocarbon receptor (AhR), pharmaceuticalcompositions comprising one or more of these compounds, or use of thesecompounds and compositions in treating diseases and conditions inpatients who can benefit from modulation of AhR activities.

Provided herein is a compound having the structure of formula 2, or apharmaceutically acceptable salt thereof:

wherein:

-   -   X₁ is N (nitrogen), O (oxygen), S (sulfur), or C (carbon); X₂ is        N (nitrogen), O (oxygen), S (sulfur), or C (carbon); X₃ is N        (nitrogen), O (oxygen), S (sulfur), or C (carbon); and X₄ is N        (nitrogen), O (oxygen), S (sulfur), or C (carbon), such that at        least one of X₁, X₂, X₃ and X₄ is N, each of X₁, X₂, X₃ and X₄        is optionally selected to form a heteroaromatic, wherein the        bond between X₁ and the adjacent carbon, between X₂ and the        adjacent carbon, between X₁ and X₄, between X₂ and X₃, and        between X₃ and X₄, can be a single bond or a double bond and the        valence of X₁, X₂, X₃ and X₄ is completed with H or C₁-C₆ alkyl        (i.e., the ring can be aromatic, partially saturated, or        saturated);    -   Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇,        Z₅ is N or CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than        two of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ are N;    -   R₂ is OR_(O), N(R_(N))₂, or SR_(S);    -   R_(O) is H, CN, substituted or unsubstituted alkyl, alkenyl,        alkynyl, aryl, alkanoyl, carbonyloxy, carbonylthio, or        carbonylamino, wherein the alkyl, alkenyl, alkynyl, or alkanoyl        is optionally interrupted by O, S, or NR (in which NR can be        N-C1-C6 alkyl), or a phosphate moiety;    -   R_(S) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;    -   each R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;        and    -   R_(3a) is selected from the group consisting of hydrogen,        deuterium, cyano, or C1-C6 alkyl;    -   R₃ is selected from the group consisting of deuterium, cyano,        formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl,        alkynyl, haloalkynyl, C₁-C₆ acyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀ is        directly connected to S), wherein R₁₀ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R₄, R₅, R₆, R₇, R₈, and R₉ are each independently selected from        the group consisting of hydrogen, deuterium, halo, amino,        hydroxy, cyano, formyl, furyl, nitro, alkyl, haloalkyl, alkenyl,        haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is        directly connected to S), wherein R₁₁ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b)        is H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆        acyloxy, amino, or C₁-C₆ acyl, R₂ preferably can be ═O, R₃        preferably can be —OR, wherein R is H or C₁-C₆ alkyl, or    -   R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein        R_(b) and R_(c) are each independently H, C₁-C₆ alkyl, alkoxy        (—O-alkyl), thioalkoxy (—S-alkyl), cyano (—CN), or amino, R₂        preferably can be ═O, R₃ preferably can be —OR, wherein R is H        or C₁-C₆ alkyl, or    -   R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S, R₂        and R₃ preferably can be each independently —OR or —NR_(a)R_(b),        wherein R, R_(a), and R_(b) are each independently H, C₁-C₆        alkyl, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are each independently selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, cyano,        formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl,        alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and        —S(O)_(n)R₁₂ (n=0 to 2, R₁₂ is directly connected to S), wherein        R₁₂ is selected from the group consisting of hydrogen,        deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,        haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy,        alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,        haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,        carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, and        halothiocarbonylthio;    -   wherein the compound is enantiomerically pure at the carbon        substituted with R₂/R₃/R_(3a), and optionally, adjacent R        groups, together, can form a three- to twelve-membered ring.

Also provided herein is a compound having the structure of formula 2a,or a pharmaceutically acceptable salt thereof:

wherein:

-   -   X is either O (oxygen) or S (sulfur);    -   Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇,        Z₅ is N or CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than        two of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ are N;    -   R₂ is OR_(O), N(R_(N))₂, or SR_(S);    -   R_(O) is H, CN, substituted or unsubstituted alkyl, alkenyl,        alkynyl, aryl, alkanoyl, carbonyloxy, carbonylthio, or        carbonylamino, wherein the alkyl, alkenyl, alkynyl, or alkanoyl        is optionally interrupted by O, S, or NR (in which NR can be        N-C1-C6 alkyl), or a phosphate moiety;    -   R_(S) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;    -   each R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;        and    -   R_(3a) is selected from the group consisting of hydrogen,        deuterium, cyano, or C1-C6 alkyl;    -   R₃ is selected from the group consisting of deuterium, cyano,        formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl,        alkynyl, haloalkynyl, C1-C6 acyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀ is        directly connected to S), wherein R₁₀ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R₄, R₅, R₆, R₇, R₈, and R₉ are each independently selected from        the group consisting of hydrogen, deuterium, halo, amino,        hydroxy, cyano, formyl, furyl, nitro, alkyl, haloalkyl, alkenyl,        haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is        directly connected to S), wherein R₁₁ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b)        is H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆        acyloxy, amino, or C₁-C₆ acyl, R₂ preferably can be ═O, R₃        preferably can be —OR, wherein R is H or C₁-C₆ alkyl, or    -   R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein        R_(b) and R_(c) are each independently H, C₁-C₆ alkyl, alkoxy        (—O-alkyl), thioalkoxy (—S-alkyl), cyano (—CN), or amino, R₂        preferably can be ═O, R₃ preferably can be —OR, wherein R is H        or C₁-C₆ alkyl, or    -   R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S, R₂        and R₃ preferably can be each independently —OR or —NR_(a)R_(b),        wherein R, R_(a), and R_(b) are each independently H, C₁-C₆        alkyl, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are each independently selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, cyano,        formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl,        alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and        —S(O)_(n)R₁₂ (n=0 to 2, R₁₂ is directly connected to S), wherein        R₁₂ is selected from the group consisting of hydrogen,        deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,        haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy,        alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,        haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,        carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, and        halothiocarbonylthio;    -   wherein the compound is enantiomerically pure at the carbon        substituted with R₂/R₃/R_(3a), and optionally, adjacent R        groups, together, can form a three- to twelve-membered ring.

Also provided herein is a compound having the structure of formula 3, ora pharmaceutically acceptable salt thereof:

wherein:

-   -   X₁ is N (nitrogen), O (oxygen), S (sulfur), or C (carbon); X₂ is        N (nitrogen), O (oxygen) S (sulfur), or C (carbon); X₃ is N        (nitrogen), O (oxygen), S (sulfur) or C (carbon); and X₄ is N        (nitrogen) O (oxygen), S (sulfur), or C (carbon), such that at        least one of X₁, X₂, X₃ and X₄ is N, each of X₁, X₂, X₃ and X₄        is optionally selected to form a heteroaromatic, wherein the        bond between X₁ and the adjacent carbon, between X₂ and the        adjacent carbon, between X₁ and X₄, between X₂ and X₃, and        between X₃ and X₄ can be a single bond or a double bond and the        valence of X₁, X₂, X₃ and X₄ is completed with H or C₁-C₆ alkyl        (i.e., the ring can be aromatic, partially saturated, or        saturated);    -   Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇,        Z₅ is N or CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than        two of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ are N;    -   R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b)        is H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆        acyloxy, amino, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein        R_(b) and R_(c) are each independently H, C₁-C₆ alkyl, alkoxy        (—O-alkyl), thioalkoxy (—S-alkyl), cyano (—CN), or amino, or    -   R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S,        wherein R_(a) is H, C₁-C₆ alkyl, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are each independently selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, cyano,        formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl,        alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and        —S(O)_(n)R₁₂ (n=0 to 2, R₁₂ is directly connected to S), wherein        R₁₂ is selected from the group consisting of hydrogen,        deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,        haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy,        alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,        haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,        carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, and        halothiocarbonylthio; and    -   R₂ and R₉ are each independently selected from the group        consisting of hydrogen, aryl, heteroaryl, cycloalkyl,        heterocycloalkyl, alkyl, —NR_(2a)C(O)OR_(2b),        —NR_(2a)C(O)R_(2b), —(C₀-C₆ alkyl)-CONHSO₂R_(2a), —(C₀-C₆        alkyl)-CONHSO₂NR_(2a)R_(2b), —(C₀-C₆ alkyl)-SO₂NHCOR_(2a),        —(C₀-C₆ alkyl)-SO₂NHR_(2a), —(C₀-C₆ alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀is directly connected to S), wherein R₁₀ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio, whereinR_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino,wherein the compound is enantiomerically pure in the R₂ or R₉ moiety;

-   -   R₄, R₅, R₆, R₇, and R₈ are each independently selected from the        group consisting of hydrogen, deuterium, halo, amino, hydroxy,        cyano, formyl, furyl, nitro, alkyl, haloalkyl, alkenyl,        haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is        directly connected to S), wherein R₁₁ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;        and    -   optionally, adjacent R groups, together, can form a three- to        twelve-membered ring.

Further provided herein is a compound having the structure of formula3a, or a pharmaceutically acceptable salt thereof:

wherein:

-   -   X is either O (oxygen) or S (sulfur);    -   Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇,        Z₅ is N or CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than        two of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ are N;    -   R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b)        is H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆        acyloxy, amino, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein        R_(b) and R_(c) are each independently H, C₁-C₆ alkyl, alkoxy        (—O-alkyl), thioalkoxy (—S-alkyl), cyano (—CN), or amino, or    -   R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S,        wherein R_(a) is H, C₁-C₆ alkyl, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are each independently selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, cyano,        formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl,        alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and        —S(O)_(n)R₁₂ (n=0 to 2, R₁₂ is directly connected to S), wherein        R₁₂ is selected from the group consisting of hydrogen,        deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,        haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy,        alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,        haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,        carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, and        halothiocarbonylthio; and    -   R₂ and R₉ are each independently selected from the group        consisting of hydrogen, aryl, heteroaryl, cycloalkyl,        heterocycloalkyl, alkyl, —NR_(2a)C(O)OR_(2b),        —NR_(2a)C(O)R_(2b), —(C₀-C₆ alkyl)-CONHSO₂R_(2a), —(C₀-C₆        alkyl)-CONHSO₂NR_(2a)R_(2b), —(C₀-C₆ alkyl)-SO₂NHCOR_(2a),        —(C₀-C₆ alkyl)-SO₂NHR_(2a), —(C₀-C₆ alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀is directly connected to S), wherein R₁₀ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio, whereinR_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino,wherein the compound is enantiomerically pure in the R₂ or R₉ moiety;

-   -   R₄, R₅, R₆, R₇, and R₈ are each independently selected from the        group consisting of hydrogen, deuterium, halo, amino, hydroxy,        cyano, formyl, furyl, nitro, alkyl, haloalkyl, alkenyl,        haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is        directly connected to S), wherein R₁₁ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;        and    -   optionally, adjacent R groups, together, can form a three- to        twelve-membered ring.

Provided further herein is a compound having the structure of formula3b, or a pharmaceutically acceptable salt thereof:

wherein:

-   -   X is either O (oxygen) or S (sulfur);    -   Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇,        Z₅ is N or CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than        two of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ are N;    -   R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b)        is H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆        acyloxy, amino, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein        R_(b) and R_(c) are each independently H, C₁-C₆ alkyl, alkoxy        (—O-alkyl), thioalkoxy (—S-alkyl), cyano (—CN), or amino, or    -   R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S,        wherein R_(a) is H, C₁-C₆ alkyl, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are each independently selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, cyano,        formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl,        alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and        —S(O)_(n)R₁₂ (n=0 to 2, R₁₂ is directly connected to S), wherein        R₁₂ is selected from the group consisting of hydrogen,        deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,        haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy,        alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,        haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,        carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, and        halothiocarbonylthio; and    -   R₂ and R₉ are each independently selected from the group        consisting of hydrogen, aryl, heteroaryl, cycloalkyl,        heterocycloalkyl, alkyl, —NR_(2a)C(O)OR_(2b),        —NR_(2a)C(O)R_(2b), —(C₀-C₆ alkyl)-CONHSO₂R_(2a), —(C₀-C₆        alkyl)-CONHSO₂NR_(2a)R_(2b), —(C₀-C₆ alkyl)-SO₂NHCOR_(2a),        —(C₀-C₆ alkyl)-SO₂NHR_(2a), —(C₀-C₆ alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀is directly connected to S), wherein R₁₀ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio, whereinR_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino,wherein the compound is enantiomerically pure in the R₂ or R₉ moiety;

-   -   R₄, R₅, R₆, R₇, and R₈ are each independently selected from the        group consisting of hydrogen, deuterium, halo, amino, hydroxy,        cyano, formyl, furyl, nitro, alkyl, haloalkyl, alkenyl,        haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is        directly connected to S), wherein R₁₁ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;        and    -   optionally, adjacent R groups, together, can form a three- to        twelve-membered ring.

Provided herein is also a compound having the structure of formula 3c,or a pharmaceutically acceptable salt thereof:

wherein:

-   -   X₁ is N (nitrogen), O (oxygen), S (sulfur), or C (carbon); X₂ is        N (nitrogen), O (oxygen) S (sulfur), or C (carbon); X₃ is N        (nitrogen), O (oxygen), S (sulfur) or C (carbon); and X₄ is N        (nitrogen) O (oxygen), S (sulfur), or C (carbon), such that at        least one of X₁, X₂, X₃ and X₄ is N, each of X₁, X₂, X₃ and X₄        is optionally selected to form a heteroaromatic, wherein the        bond between X₁ and the adjacent carbon, between X₂ and the        adjacent carbon, between X₁ and X₄, between X₂ and X₃, and        between X₃ and X₄ can be a single bond or a double bond and the        valence of X₁, X₂, X₃ and X₄ is completed with H or C₁-C₆ alkyl        (i.e., the ring can be aromatic, partially saturated, or        saturated);    -   Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇,        Z₅ is N or CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than        two of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ are N;    -   R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b)        is H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆        acyloxy, amino, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein        R_(b) and R_(c) are each independently H, C₁-C₆ alkyl, alkoxy        (—O-alkyl), thioalkoxy (—S-alkyl), cyano (—CN), or amino, or    -   R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S,        wherein R_(a) is H, C₁-C₆ alkyl, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are each independently selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, cyano,        formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl,        alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and        —S(O)_(n)R₁₂ (n=0 to 2, R₁₂ is directly connected to S), wherein        R₁₂ is selected from the group consisting of hydrogen,        deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,        haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy,        alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,        haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,        carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, and        halothiocarbonylthio; and    -   R₂ and R₉ are each independently selected from the group        consisting of hydrogen, aryl, heteroaryl, cycloalkyl,        heterocycloalkyl, alkyl, —NR_(2a)C(O)OR_(2b),        —NR_(2a)C(O)R_(2b), —(C₀-C₆ alkyl)-CONHSO₂R_(2a), —(C₀-C₆        alkyl)-CONHSO₂NR_(2a)R_(2b), —(C₀-C₆ alkyl)-SO₂NHCOR_(2a),        —(C₀-C₆ alkyl)-SO₂NHR_(2a), —(C₀-C₆ alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀is directly connected to S), wherein R₁₀ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio, whereinR_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino,wherein the compound is enantiomerically pure in the R₂ or R₉ moiety;

-   -   R₄, R₅, R₆, R₇, and R₈ are each independently selected from the        group consisting of hydrogen, deuterium, halo, amino, hydroxy,        cyano, formyl, furyl, nitro, alkyl, haloalkyl, alkenyl,        haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is        directly connected to S), wherein R₁₁ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;        and    -   optionally, adjacent R groups, together, can form a three- to        twelve-membered ring.

Also provided herein is a compound having the structure of formula 4, ora pharmaceutically acceptable salt thereof:

wherein:

-   -   X is O (oxygen) or S (sulfur);    -   Y is a bond, O (oxygen), S (sulfur), or

-   -   Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇,        Z₅ is N or CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than        two of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ are N;    -   R₄, R₅, R₆, R₇, R₈, and R₉ are each independently selected from        the group consisting of hydrogen, deuterium, halo, amino,        hydroxy, cyano, formyl, furyl, nitro, alkyl, haloalkyl, alkenyl,        haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is        directly connected to S), wherein R₁₁ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R₂ is OR_(O), N(R_(N))₂, or SR_(S);    -   R_(O) is H, CN, substituted or unsubstituted alkyl, alkenyl,        alkynyl, aryl, alkanoyl, carbonyloxy, carbonylthio, or        carbonylamino, wherein the alkyl, alkenyl, alkynyl, or alkanoyl        is optionally interrupted by O, S, or NR (in which NR can be        N—C₁-C₆ alkyl), or a phosphate moiety;    -   R_(S) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;    -   each R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;    -   R_(3a) is selected from the group consisting of hydrogen,        deuterium, cyano, or C₁-C₆ alkyl;    -   R₃ is selected from the group consisting of deuterium, cyano,        formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl,        alkynyl, haloalkynyl, C₁-C₆ acyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀ is        directly connected to S), wherein R₁₀ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   wherein the compound is enantiomerically pure at the carbon        substituted with R₂/R₃/R_(3a); and optionally, adjacent R        groups, together, can form a three- to twelve-membered ring.

Further provided herein is a compound having the structure of formula 5,or a pharmaceutically acceptable salt thereof:

wherein:

-   -   X is O (oxygen) or S (sulfur);    -   Y is a bond, O (oxygen), S (sulfur), or

-   -   Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇,        Z₅ is N or CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than        two of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ are N;    -   R₂ and R₉ are each independently selected from the group        consisting of hydrogen, aryl, heteroaryl, cycloalkyl,        heterocycloalkyl, alkyl, —NR_(2a)C(O)OR_(2b),        —NR_(2a)C(O)R_(2b), —(C₀-C₆ alkyl)-CONHSO₂R_(2a), —(C₀-C₆        alkyl)-CONHSO₂NR_(2a)R_(2b), —(C₀-C₆ alkyl)-SO₂NHCOR_(2a),        —(C₀-C₆ alkyl)-SO₂NHR_(2a), —(C₀-C₆ alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀is directly connected to S), wherein R₁₀ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio, whereinR_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino,wherein the compound is enantiomerically pure in the R₂ or R₉ moiety;

-   -   R₄, R₅, R₆, R₇, and R₈ are each independently selected from the        group consisting of hydrogen, deuterium, halo, amino, hydroxy,        cyano, formyl, furyl, nitro, alkyl, haloalkyl, alkenyl,        haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is        directly connected to S), wherein R₁₁ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;        and    -   optionally, adjacent R groups, together, can form a three- to        twelve-membered ring.

Also provided herein is a compound having the structure of formula 6, ora pharmaceutically acceptable salt thereof:

wherein:

-   -   Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇,        Z₅ is N or CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than        two of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ are N;    -   R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b)        is H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆        acyloxy, amino, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein        R_(b) and R_(c) are each independently H, C₁-C₆ alkyl, alkoxy        (—O-alkyl), thioalkoxy (—S-alkyl), cyano (—CN), or amino, or    -   R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S,        wherein R_(a) is H, C₁-C₆ alkyl, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are each independently selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, cyano,        formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl,        alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and        —S(O)_(n)R₁₄ (n=0 to 2, R₁₄ is directly connected to S), wherein        R₁₄ is selected from the group consisting of hydrogen,        deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,        haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy,        alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,        haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,        carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, and        halothiocarbonylthio;    -   R₄, R₅, R₆, R₇, and R₈ are each independently selected from the        group consisting of hydrogen, deuterium, halo, amino, hydroxy,        cyano, formyl, furyl, nitro, alkyl, haloalkyl, alkenyl,        haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is        directly connected to S), wherein R₁₁ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;    -   B₁, B₂, B₃, B₄, B₅, and B₆ are each independently C or N;    -   R₉ and R₁₀, the number of which, together, complete the valence        of each of B₁, B₂, B₃, B₄, B₅, and B₆, are each independently        selected from the group consisting of hydrogen, aryl,        heteroaryl, cycloalkyl, heterocycloalkyl, alkyl,        —NR_(2a)C(O)OR_(2b), —NR_(2a)C(O)R_(2b), —(C₀-C₆        alkyl)-CONHSO₂R_(2a), —(C₀-C₆ alkyl)-CONHSO₂NR_(2a)R_(2b),        —(C₀-C₆ alkyl)-SO₂NHCOR_(2a), —(C₀-C₆ alkyl)-SO₂NHR_(2a)—(C₀-C₆        alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₂ (n=0 to 2, R₁₂is directly connected to S), wherein R₁₂ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and

wherein R_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino, R₂and R₃ are each independently selected from the group consisting of—NR_(a)R_(b) (R_(a) and R_(b) are each independently H, C₁-C₆ alkyl, orC₁-C₆ acyl), hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl,furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, C₁-C₆ acyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl,carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R13 (n=0 to 2, R₁₃ is directlyconnected to S), wherein R₁₃ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio, wherein the compound isenantiomerically pure in the R₉ or R₁₀ moiety; and

-   -   optionally, adjacent R groups, together, can form a three- to        twelve-membered ring.

In each of formulae 2, 2a, 3, 3a, 3b, 3c, 4, 5, and 6, in someembodiments, each of R₄, R₅, R₆, and R₇ is hydrogen. In otherembodiments, at least one of R₄, R₅, R₆, and R₇ can be F, C₁, or Br, andthe others of R₄, R₅, R₆, and R₇ are hydrogen. In still otherembodiments, at least two of R₄, R₅, R₆, and R₇, independently, can beF, Cl, or Br, and the others of R₄, R₅, R₆, and R₇ are hydrogen. The F,Cl, or Br can be at the indole ring carbon 5, 6, or 7.

In each of formulae 2a, 3, 3a, 3b, 3c, 4, 5, and 6, in certainembodiments, R₉ can be hydrogen. R₂ can be acyl, cyano,hydroxyl-substituted C₁-C₆ alkyl, amino-substituted C₁-C₆ alkyl, aryl,or heteroaryl. The aryl or heteroaryl can be substituted orunsubstituted. The substituted aryl or heteroaryl can be substitutedwith halo, amino, hydroxyl, or C₁-C₆ alkyl. The amino can beunsubstituted.

In each of formulae 2, 2a, and 4, in certain embodiments, R₂ can beester.

In each of formulae 2, 2a, and 4, in certain embodiments, R₂ can behydroxyl or amino and R₃ can be alkyl, aryl, nitro, or cyano. R₉ can behydrogen. The amino can be substituted or unsubstituted.

In some embodiments, the invention provides a compound having thestructure of formula 8a, 8b, 8c, or 8d, or a pharmaceutically acceptablesalt thereof:

wherein:

-   -   R₄, R₅, R₆, and R₇, are each independently selected from the        group consisting of hydrogen and halo;    -   R_(o) is hydrogen, deuterium, alkyl, aryl, or acyl; and    -   R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety.

In one embodiment, R_(o) is H or alkyl. In another embodiment, R_(o) isacyl, for example, a substituted or unsubstituted C₁-C₆ acyl. Thesubstituted or unsubstituted C₁-C₆ acyl can be a substituted C₂, C₃, C₄,C₅, or C₆ acyl, optionally interrupted by O, S, or NR (in which NR canbe N—C₁-C₆ alkyl). The substituent can be a halo, carboxyl, amino,hydroxyl, alkoxy, or phosphonate moiety. The amino moiety can be adialkylamino moiety, for example, dimethylamino, morpholino, piperazinylor bipiperidinyl.

In one embodiment of the compound of structural formula 8a or 8b, atleast one of R₄, R₅, R₆, and R₇ is F, Cl, or Br, and the others of R₄,R₅, R₆, and R₇ are hydrogen. In another embodiment, at least two of R₄,R₅, R₆, and R₇ are F, Cl, or Br, and the others of R₄, R₅, R₆, and R₇are hydrogen.

In one embodiment, R₅ is F, and R₄, R₆, and R₇ are hydrogen. In anotherembodiment, R₆ is F, and R₄, R₅, and R₇ are hydrogen. In still anotherembodiment, R₇ is F, and R₄, R₅, and R₆ are hydrogen.

In one embodiment, R₅ is Cl, and R₄, R₆, and R₇ are hydrogen. In anotherembodiment, R₆ is Cl, and R₄, R₅, and R₇ are hydrogen. In still anotherembodiment, R₇ is Cl, and R₄, R₅, and R₆ are hydrogen.

In one embodiment, R₅ and R₆ are F, and R₄ and R₇ are hydrogen. Inanother embodiment, R₅ and R₇ are F, and R₄ and R₆ are hydrogen. Instill another embodiment, R₆ and R₇ are F, and R₄ and R₅ are hydrogen.

In one embodiment, R₅ and R₆ are C₁, and R₄ and R₇ are hydrogen. Inanother embodiment, R₅ and R₇ are C₁, and R₄ and R₆ are hydrogen. Instill another embodiment, R₆ and R₇ are C₁, and R₄ and R₅ are hydrogen.

In some embodiments, each of R₄, R₅, R₆, and R₇ is hydrogen.

In some embodiments, R_(N) can be a phosphate moiety. The phosphatemoiety can have the structure

wherein n can be 0, 1, 2, 3, 4, 5, or 6, R_(x) can be H or C₁-C₆ alkyl,R_(y) can be H or C₁-C₆ alkyl, or, together, R_(x) and R_(y) form aC₃-C₈ cycloalkyl, and Q₁ ⁺ and Q₂ ⁺ can be each, independently, amonocation, or together can be a dication or one of Q₁ ⁺ or Q₂ ⁺ can beC₁-C₆ alkyl, benzyl, allyl or —(CR₂R₃—O)—R₂₃, and each of R₂, R₃, andR₂₃ can be, independently, H, or C₁-C₆ alkyl. In certain embodiments,the phosphate moiety can be a phosphorous-containing aralkyl group, forexample a benzyl group.

In some embodiments, n can be 0 or 1.

In certain circumstances, Q₁ ⁺ and Q₂ ⁺ can be each, independently, analkali metal.

In certain circumstances, Q₁ ⁺ and Q₂ ⁺ can be each, independently,selected from the group consisting of lithium, sodium, potassium,ammonium, alkyl ammonium, and phosphonium.

In certain circumstances, Q₁ ⁺ and Q₂ ⁺ together can be selected fromthe group consisting of an alkaline earth metal salt.

In certain circumstances, Q₁ ⁺ and Q₂ ⁺ can be each independentlyselected from the group consisting of zinc, calcium and magnesium.

In some embodiments, the present disclosure provides a compound selectedfrom a compound in Table 1 (ARI-164), or a pharmaceutically acceptablesalt thereof. In some embodiments, the present disclosure provides acompound selected from a compound in Table 1 (ARI-165), or apharmaceutically acceptable salt thereof. In some embodiments, thepresent disclosure provides a compound selected from a compound in Table1 (ARI-186), or a pharmaceutically acceptable salt thereof. In someembodiments, the present disclosure provides a compound selected from acompound in Table 1 (ARI-092), or a pharmaceutically acceptable saltthereof. In some embodiments, the present disclosure provides a compoundselected from a compound in Table 1 (ARI-192), or an enantiomer orpharmaceutically acceptable salt thereof. In some embodiments, thepresent disclosure provides a compound selected from a compound in Table1 (ARI-193), or an enantiomer or pharmaceutically acceptable saltthereof. In some embodiments, the present disclosure provides a compoundselected from a compound in Table 1 (ARI-196), or an enantiomer orpharmaceutically acceptable salt thereof. In some embodiments, thepresent disclosure provides a compound selected from a compound in Table1 (ARI-197), or an enantiomer or pharmaceutically acceptable saltthereof. In some embodiments, the present disclosure provides a compoundselected from a compound in Table 1 (ARI-198), or an enantiomer orpharmaceutically acceptable salt thereof. In some embodiments, thepresent disclosure provides a compound selected from a compound in Table1 (ARI-199), or an enantiomer or pharmaceutically acceptable saltthereof. In some embodiments, the present disclosure provides a compoundselected from a compound in Table 1 (ARI-205), or an enantiomer orpharmaceutically acceptable salt thereof.

The present disclosure also provides a pharmaceutical compositioncomprising a compound described herein and a pharmaceutically acceptablecarrier.

The present disclosure provides a method of stimulating the immunesystem in a patient in need thereof, comprising administering to thepatient a therapeutically effective amount of a compound orpharmaceutical composition described herein. In some embodiments, thepatient has an increased count of cells selected from the groupconsisting of white blood cells, macrophages, neutrophils, lymphocytes(e.g., B lymphocytes and/or T lymphocytes), natural killer (NK) cells,dendritic cells, and platelets, or increased levels of cytokinesindicative of a stimulated immune system after the administering step.In some embodiments, the compound decreases IL-21 level in the patient.In some embodiments, the patient has cancer.

The present disclosure also provides a method of treating cancer in apatient, comprising administering to the patient a therapeuticallyeffective amount of a compound described herein. In some embodiments,the cancer is a hematological malignancy (e.g., a lymphoma, leukemia, ormyeloma), or a solid tumor. In some embodiments, the cancer may beselected from the group consisting of diffuse large B-cell lymphoma,marginal zone lymphoma, chronic lymphocytic leukemia (CLL), smalllymphocytic lymphoma, prolymphocytic leukemia, acute lymphocyticleukemia, Waldenström's Macroglobulinemia (WM), follicular lymphoma,mantle cell lymphoma (MCL), Hodgkin lymphoma, non-Hodgkin lymphoma,multiple myeloma, prostate cancer, ovarian cancer, fallopian tubecancer, cervical cancer, breast cancer, lung cancer (e.g., non-smallcell lung cancer), skin cancer (e.g., melanoma), colorectal cancer,stomach cancer, pancreatic cancer, liver cancer, kidney cancer, bladdercancer, soft tissue cancer, glioma, and head and neck cancer. In someembodiments, the method further comprises administering to the patientanother cancer therapeutic agent, e.g., an immune checkpoint inhibitor(e.g., a PD-1, PD-L1, and/or PD-L2 inhibitor). In some embodiments, themethod further comprises administering one or more maintenance doses ofthe compound while the patient is in remission.

Also provided herein is a compound or pharmaceutical compositiondescribed herein for use in modulating or stimulating the immune system(e.g., in patients with immune dysregulation or autoimmune diseases suchas multiple sclerosis, rheumatoid arthritis, systemic lupuserythematosus, Crohn's disease, ulcerative colitis, or psoriasis) ortreating cancer in a patient in need thereof in a treatment methoddescribed herein.

The present disclosure further provides the use of a compound describedherein for the manufacture of a medicament for modulating or stimulatingthe immune system or treating cancer in a patient in need thereof in atreatment method described herein.

The present disclosure also provides articles of manufacture, includingkits, that comprise a compound described herein.

The present disclosure also provides a method of making a compound ofStructural Formula 9, or an enantiomer, diastereomer, orpharmaceutically acceptable salt thereof:

wherein:

-   -   Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇,        Z₅ is N or CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than        two of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ are N;    -   R₄, R₅, R₆, R₇, R₈, and R₉ are each independently selected from        the group consisting of hydrogen, deuterium, halo, amino,        hydroxy, cyano, formyl, furyl, nitro, alkyl, haloalkyl, alkenyl,        haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is        directly connected to S), wherein R₁₁ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R₃ is selected from the group consisting of deuterium, cyano,        formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl,        alkynyl, haloalkynyl, C₁-C₆ acyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀ is        directly connected to S), wherein R₁₀ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R_(3a) is selected from the group consisting of hydrogen,        deuterium, cyano, or C₁-C₆ alkyl;    -   R_(o) is hydrogen, deuterium, alkyl, aryl, or acyl;    -   each R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;    -   and optionally, adjacent R groups, together, can form a three-        to twelve-membered ring; comprising:    -   (i) contacting a compound of Structural Formula 10 with        (S)-2-methylpropane-2-sulfinamide in the presence of a catalyst        to yield a compound of Structural Formula 11;

-   -   (ii) contacting a compound of Structural Formula 11 with a one        or more alkylating agent(s) to yield a compound of Structural        Formula 12;

-   -   (iii) contacting a compound of Structural Formula 12 with a        compound of Structural Formula 13 in the presence of an        organolithium base to yield a compound of Structural Formula 14;

-   -   (iv) subjecting a compound of Structural Formula 14 to acid-base        hydrolysis to obtain a compound of Structural Formula 9.

In some embodiments, each of R₄, R₅, R₆, R₇, R₈, R₉, and R_(N) ishydrogen.

In some embodiments, at least one of R₄, R₅, R₆, and R₇ is F, Cl, or Brand the others of R₄, R₅, R₆, and R₇ are hydrogen.

In some embodiments, R_(o), R₃, and R_(3a) are independently H or alkyl.

In some embodiments, at least one of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, or Z₇ is N.

In some embodiments, the compound of Structural formula 9 isenantiomerically pure at the carbon substituted with NHR_(o)/R₃/R_(3a).

In some embodiments, R₃ and R_(3a) together form a three- totwelve-membered ring, including a cyclopropyl, cyclobutyl, cyclopentyl,or cyclohexyl ring.

In some embodiments, the catalyst is a transition metal alkoxide.

In particular embodiments, the transition metal alkoxide is a titaniumalkoxide.

The present disclosure also provides a method of making(S)-(4-(1-aminopropyl)thiazol-2-yl)(6-fluoro-1H-indol-3-yl)methanone,comprising:

-   -   contacting thiazole-4-carbaldehyde with        (S)-2-methylpropane-2-sulfinamide in the presence of titanium        isopropoxide to yield        (S,E)-2-methyl-N-(thiazol-4-ylmethylene)propane-2-sulfinamide;    -   contacting        (S,E)-2-methyl-N-(thiazol-4-ylmethylene)propane-2-sulfinamide        with ethylmagnesium bromide to yield        (S)-2-methyl-N-(1-(thiazol-4-yl)propyl)propane-2-sulfinamide;    -   contacting        (S)-2-methyl-N-(1-(thiazol-4-yl)propyl)propane-2-sulfinamide        with tert-butyl        6-fluoro-3-(methoxy(methyl)carbamoyl)-1H-indole-1-carboxylate in        the presence of an organolithium base to yield        (S)—N-((S)-1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propyl)-2-methylpropane-2-sulfinamide;        and    -   subjecting        (S)—N-((S)-1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propyl)-2-methylpropane-2-sulfinamide        to acid-base hydrolysis to obtain        (S)-(4-(1-aminopropyl)thiazol-2-yl)(6-fluoro-1H-indol-3-yl)methanone.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a synthesis scheme for ARI-164 and ARI-165 according toExample 1.

FIG. 2 shows a synthesis scheme for ARI-164 and ARI-165 according toExample 2

FIG. 3 shows a synthesis scheme for ARI-092 and ARI-094 according toExample 3.

FIG. 4 shows a chiral synthesis scheme for ARI-164 and ARI-165 accordingto Example 4.

FIG. 5 shows a synthesis scheme for PTC17341-138 and PTC17341-139according to Example 5.

FIG. 6 shows a synthesis scheme for PTC17341-133A and PTC17341-133Baccording to Example 6.

FIG. 7A shows a synthesis scheme for compounds ARI-196, ARI-197,ARI-198, ARI-199, and ARI-205 according to Examples 9-13.

FIG. 7B shows a synthesis scheme for compound ARI-192 according toExample 14.

FIG. 7C shows a synthesis scheme for compound ARI-193 according toExample 15.

FIG. 8 shows a synthesis scheme for compound ARI-075 according toExample 16.

FIG. 9 shows a synthesis scheme for compound ARI-209 according toExample 18.

FIG. 10 shows a synthesis scheme for compound ARI-215 according toExample 20.

FIG. 11 shows a synthesis scheme for compound ARI-221 according toExample 22.

FIG. 12 shows a synthesis scheme for compound ARI-225 according toExample 23.

FIG. 13 shows a synthesis scheme for compound ARI-226 according toExample 24.

FIG. 14 shows a synthesis scheme for compound ARI-217 according toExample 25.

FIG. 15A shows a synthesis scheme for compound ARI-186 according toExample 26.

FIG. 15B shows a synthesis scheme for compound ARI-232 according toExample 27.

FIG. 15C shows a synthesis scheme for compound ARI-233 according toExample 28.

FIG. 15D shows a synthesis scheme for compound ARI-234 according toExample 29.

FIG. 15E shows a synthesis scheme for compound ARI-235 according toExample 30.

FIG. 15F shows a synthesis scheme for compound ARI-236 according toExample 31.

FIG. 16A is a plot showing the mean plasma concentration-time profile ofARI-186 following IV administration of 5 mg/kg in Balb/C mice.

FIGS. 16B and 16C are plots showing the mean plasma concentration-timeprofiles of ARI-186 following PO administration of 10 mg/kg or 40 mg/kgin Balb/C mice.

FIG. 16D is a plot showing the mean plasma concentration-time profile ofARI-186 following IP administration of 40 mg/kg in Balb/C mice.

FIGS. 17A and 17B are plots showing individual plasma concentration-timeprofiles of ARI-186 following PO administration of 10 mg/kg in SD ratson days 1 and 5, respectively.

FIGS. 18A and 18B are plots showing individual plasma concentration-timeprofiles of ARI-224 following PO administration of 10 mg/kg in SD ratson days 1 and 5, respectively.

FIGS. 19A and B are plots showing individual plasma concentration-timeprofiles of ARI-226 following PO administration of 10 mg/kg in SD ratson days 1 and 5, respectively.

FIGS. 20A and 20B are plots comparing the tumor inhibitory activities ofARI-143, ARI-164 and ARI-165 in the EMT-6 syngeneic mouse tumor model.

FIG. 20C is a plot comparing the tumor inhibitory activities of ARI-164(80 mpk) and ARI-186 (20 mpk) in the Pan02 syngeneic mouse tumor model.

FIGS. 21A-G are plots comparing the tumor inhibitory activities ofARI-164, anti-PD-1, and their combination in the 4T-1, A20, EMT-6,Pan02, H22, LL/2, and MC38 syngeneic mouse tumor models.

DETAILED DESCRIPTION OF THE INVENTION

All technical and scientific terms used herein are the same as thosecommonly used by those ordinary skilled in the art to which the presentinvention pertains unless defined specifically otherwise.

The moieties described below can be substituted or unsubstituted.“Substituted” refers to replacement of a hydrogen atom of a molecule oran R-group with one or more additional R-groups such as deuterium,halogen, alkyl, haloalkyl, alkenyl, alkoxy, alkoxyalkyl, alkylthio,trifluoromethyl, acyloxy, hydroxy, hydroxyalkyl, mercapto, carboxy,cyano, acyl, aryloxy, aryl, arylalkyl, heteroaryl, amino, aminoalkyl,alkylamino, dialkylamino, morpholino, piperidino, pyrrolidin-1-yl,piperazin-1-yl, nitro, phosphine, phosphinate, phosphonate, sulfato, ═O,═S, or other R-groups. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof a group. Combinations of substituents contemplated herein arepreferably those that result in the formation of stable (e.g., notsubstantially altered for a week or longer when kept at a temperature of40° C. or lower in the absence of moisture or other chemically reactiveconditions), or chemically feasible, compounds.

“Hydroxy”, “thiol”, “cyano”, “nitro”, and “formyl” refer, respectively,to —OH, —SH, —CN, —NO₂, and —CHO.

“Acyloxy” refers to a RC(═O)O— radical, wherein R is alkyl, cycloalkyl,aryl, heteroalkyl, heteroaryl, or heterocycloalkyl, which are asdescribed herein. In some embodiments, it is a C₁-C₄ acyloxy radical,which refers to the total number of chain or ring atoms of the alkyl,cycloalkyl, aryl, heteroalkyl, heteroaryl, or heterocycloalkyl portionof the acyloxy group plus the carbonyl carbon of acyl, i.e., the otherring or chain atoms plus carbonyl. If the R radical is heteroaryl orheterocycloalkyl, the hetero ring or chain atoms contribute to the totalnumber of chain or ring atoms.

“Alkyl” refers to a group of 1-18, 1-16, 1-12, 1-10, preferably 1-8,more preferably 1-6 unsubstituted or substituted hydrogen-saturatedcarbons connected in linear, branched, or cyclic fashion, including thecombination in linear, branched, and cyclic connectivity. Non-limitingexamples include methyl, ethyl, propyl, isopropyl, butyl, and pentyl.

“Cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radicalthat contains carbon and hydrogen, and may be saturated, or partiallyunsaturated. Cycloalkyl groups include groups having from 3 to 10 ringatoms (e.g., C₃-C₁₀ cycloalkyl). Whenever it appears herein, a numericalrange such as “3 to 10” refers to each integer in the given range; e.g.,“3 to 10 carbon atoms” means that the cycloalkyl group may consist of 3carbon ring atoms, 4 carbon ring atoms, 5 carbon ring atoms, etc., up toand including 10 carbon ring atoms. In some embodiments, it is a C₃-C₈cycloalkyl radical. In some embodiments, it is a C₃-C₈ cycloalkylradical. Examples of cycloalkyl group include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloseptyl, cyclooctyl, cyclononyl, cyclodecyl, andnorbornyl. The term “cycloalkyl” also refers to spiral ring system, inwhich the cycloalkyl rings share one carbon atom.

“Heterocycloalkyl” refers to a 3- to 18-membered nonaromatic ring (e.g.,C₃-C₁₈ heterocycloalkyl) radical that comprises two to twelve ringcarbon atoms and from one to six heteroatoms selected from nitrogen,oxygen and sulfur. Whenever it appears herein, a numerical range such as“3 to 18” refers to each integer in the given range; e.g., “3 to 18 ringatoms” means that the heterocycloalkyl group may consist of 3 ringatoms, 4 ring atoms, etc., up to and including 18 ring atoms. In someembodiments, it is a C₅-C₁₀ heterocycloalkyl. In some embodiments, it isa C₄-C₁₀ heterocycloalkyl. In some embodiments, it is a C₃-C₁₀heterocycloalkyl. The heterocycloalkyl radical may be a monocyclic,bicyclic, tricyclic or tetracyclic ring system, which may include fusedor bridged ring systems. The heteroatoms in the heterocycloalkyl radicalmay be optionally oxidized. One or more nitrogen atoms, if present, mayoptionally be quaternized. The heterocycloalkyl radical may be partiallyor fully saturated. The heterocycloalkyl may be attached to the rest ofthe molecule through any atom of the ring(s). Examples of suchheterocycloalkyl radicals include, but are not limited to,6,7-dihydro-5H-cyclopenta[b]pyridine, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. In someembodiments, the heterocycloalkyl group is aziridinyl, azetidinyl,pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl,dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, indolinyl,tetrahydroquinolyl, tetrahydroisoquinolin and benzoxazinyl, preferablydihydrooxazolyl and tetrahydrofuranyl.

“Halo” refers to any of halogen atoms fluorine (F), chlorine (Cl),bromine (Br), or iodine (I). A particular example of such halo groups isfluorine.

“Haloalkyl” refers to an alkyl substituted by one or more halo(s).

“Alkenyl” refers to a group of unsubstituted or substituted hydrocarbonscontaining 2-18, 2-16, 2-12, 2-10, for example, 2-8 (e.g., 2-6) carbons,which are linear, branched, cyclic, or in combination thereof, with atleast one carbon-to-carbon double bond.

“Haloalkenyl” refers to an alkenyl substituted by one or more halo(s).

“Alkynyl” refers to a group of unsubstituted or substituted hydrocarbonscontaining 2-18, 2-16, 2-12, 2-10, for example, 2-8 (e.g., 2-6) carbons,which are linear, branched, cyclic, or in combination thereof, with atleast one carbon-to-carbon triple bond.

“Haloalkynyl” refers to an alkynyl substituted by one or more halo(s).

“Amino protecting group” refers to those groups intended to protect anamino group against undesirable reactions during synthetic proceduresand which can later be removed to reveal the amine. Commonly used aminoprotecting groups are disclosed in Protective Groups in OrganicSynthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York,N.Y., (3rd Edition, 1999). Amino protecting groups include acyl groupssuch as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl,2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,o-nitrophenoxyacetyl, alpha-chlorobutyryl, benzoyl, 4-chlorobenzoyl,4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such asbenzenesulfonyl, p-toluenesulfonyl and the like; alkoxy- oraryloxy-carbonyl groups (which form urethanes with the protected amine)such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,alpha,alpha-dimethyl-3,5-dimethoxybenzyloxycarbonyl,benzhydryloxycarbonyl, t-butyloxycarbonyl (Boc),diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl,methoxycarbonyl, allyloxycarbonyl (Alloc),2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl (Teoc),phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl(Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl,cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; aralkyl groupssuch as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silylgroups such as trimethylsilyl and the like. Amino protecting groups alsoinclude cyclic amino protecting groups such as phthaloyl anddithiosuccinimidyl, which incorporate the amino nitrogen into aheterocycle. Typically, amino protecting groups include formyl, acetyl,benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, Alloc, Teoc, benzyl,Fmoc, Boc and Cbz.

“Amino” refers to unsubstituted amino and substituted amino groups, forexample, primary amines, secondary amines, tertiary amines andquaternary amines. Specifically, “amino” refers to —NR_(a)R_(b), whereinR_(a) and R_(b), both directly connected to the N, can be independentlyselected from hydrogen, deuterium, halo, hydroxy, cyano, formyl, nitro,alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy,alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, a nitrogen protective group,—(CO)-alkyl, —(CO)—O-alkyl, or —S(O)_(n)R_(c) (n=0 to 2, R_(c) isdirectly connected to S), wherein R_(c) is independently selected fromhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, or halothiocarbonylthio.

“Aryl” refers to a C₆-C₁₄ aromatic hydrocarbon. For example, aryl can bephenyl, napthyl, or fluorenyl.

“Heteroaryl” refers to a C₆-C₁₄ aromatic hydrocarbon having one or moreheteroatoms, such as N, O, or S. The heteroaryl can be substituted orunsubstituted. Examples of a heteroaryl include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl,benzofurazanyl, benzothiazolyl, benzothienyl,benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). In some embodiments, the heteroaryl can be dithiazinyl, furyl,imidazolyl, indolyl, isoquinolinyl, isoxazolyl, oxadiazolyl (e.g.,(1,3,4)-oxadiazolyl, or (1,2,4)-oxadiazolyl), oxazolyl, pyrazinyl,pyrazolyl, pyrazyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrimidyl,pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienyl, triazinyl,(1,2,3)-triazolyl, (1,2,4)-triazolyl, 1,3,4-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl,5-amino-1,2,4-oxadiazolyl, 5-amino-1,3,4-oxadiazolyl,5-amino-1,3,4-oxadiazolyl, 3-methyl-1,2,4-oxadiazolyl,5-methyl-1,2,4-oxadiazolyl, 5-(trifluoromethyl)-1,2,4-oxadiazolyl,5-(methylamino)-1,2,4-oxadiazolyl, 5-(aminomethyl)-1,2,4-oxadiazolyl,5-(aminomethyl)-1,3,4-oxadiazolyl, 5-amino-4-cyanooxazolyl,5,6-dichloro-1H-indolyl, 5,6-difluoro-1H-indolyl, 5-chloro-1H-indolyl,5,6-dibromo-1H-indolyl, 5-fluoro-1H-indolyl, 5-methoxy-1H-indolyl,7-fluoro-1H-indolyl, 6-cyano-1H-indolyl, 5-cyano-1H-indolyl,4-fluoro-1H-indolyl, 5,6-difluoro-1H-indolyl, 6-fluoro-1H-indolyl, or5,7-difluoro-1h-indolyl.

The substituent on the heteroaryl group can be alkyl (e.g., C₁-C₆alkyl), amino, cyano, halo (e.g., fluoro, bromo, and chloro), alkylamino(e.g., C₁-C₆ alkylamino), methyleneamino, nitro, or hydroxyl. Theheteroaryl group can have two, three or four substituents.

“Carbocycle” refers to a C₆-C₁₄ cyclic hydrocarbon. For example, arylcan be phenyl, napthyl, or fluorenyl.

“Heterocycle” refers to a C₆-C₁₄ cyclic hydrocarbon having one or moreheteroatoms, such as N, O, or S.

“Alkoxy” refers to an alkyl connected to an oxygen atom (—O— alkyl).

“Haloalkoxy” refers to a haloalkyl connected to an oxygen atom (—O—haloalkyl).

“Thioalkoxy” refers to an alkyl connected to a sulfur atom (—S— alkyl).

“Halothioalkoxy” refers to a haloalkyl connected to a sulfur atom (—S—haloalkyl).

“Carbonyl” refers to —(CO)—, wherein (CO) indicates that the oxygen isconnected to the carbon with a double bond.

“Alkanoyl” or “acyl” refers to an alkyl connected to a carbonyl group[—(CO)-alkyl].

“Haloalkanoyl” or “haloacyl” refers to a haloalkyl connected to acarbonyl group [—(CO)— haloalkyl].

“Thiocarbonyl” refers to —(CS)—, wherein (CS) indicates that the sulfuris connected to the carbon with a double bond.

“Thioalkanoyl (or thioacyl)” refers to an alkyl connected to athiocarbonyl group [—(CS)— alkyl].

“Halothioalkanoyl” or “halothioacyl” refers to a haloalkyl connected toa thiocarbonyl group [—(CS)— haloalkyl].

“Carbonyloxy” refers to an alkanoyl (or acyl) connected to an oxygenatom [—O— (CO)— alkyl].

“Halocarbonyloxy” refers to a haloalkanoyl (or haloacyl) connected to anoxygen atom [—O— (CO)— haloalkyl].

“Carbonylthio” refers to an alkanoyl (or acyl) connected to a sulfuratom [—S— (CO)— alkyl].

“Halocarbonylthio” refers to a haloalkanoyl (or haloacyl) connected to asulfur atom [—S— (CO)— haloalkyl].

“Thiocarbonyloxy” refers to a thioalkanoyl (or thioacyl) connected to anoxygen atom [—O— (CS)— alkyl].

“Halothiocarbonyloxy” refers to a halothioalkanoyl (or halothioacyl)connected to an oxygen atom [—O— (CS)— haloalkyl].

“Thiocarbonylthio” refers to a thioalkanoyl (or thioacyl) connected to asulfur atom [—S— (CS)— alkyl].

“Halothiocarbonylthio” refers to a halothioalkanoyl (or halothioacyl)connected to a sulfur atom [—S— (CS)— haloalkyl].

Indole Compounds

An aspect of the present disclosure relates to indole compounds that canmodulate human aryl hydrocarbon receptor (AhR). These compounds bindspecifically to AhR. Without wishing to be bound by theory, it iscontemplated that AhR bound by one of the present compounds is agonizedwith respect to the receptor's immune-stimulatory activity.

In some embodiments, the compound has the structure of formula 2, or apharmaceutically acceptable salt thereof:

wherein:

-   -   X₁ is N (nitrogen), O (oxygen), S (sulfur), or C (carbon); X₂ is        N (nitrogen), O (oxygen) S (sulfur), or C (carbon); X₃ is N        (nitrogen), O (oxygen), S (sulfur) or C (carbon); and X₄ is N        (nitrogen) O (oxygen), S (sulfur), or C (carbon), such that at        least one of X₁, X₂, X₃ and X₄ is N, each of X₁, X₂, X₃ and X₄        is optionally selected to form a heteroaromatic, wherein the        bond between X₁ and the adjacent carbon, between X₂ and the        adjacent carbon, between X₁ and X₄, between X₂ and X₃, and        between X₃ and X₄ can be a single bond or a double bond and the        valence of X₁, X₂, X₃ and X₄ is completed with H or C₁-C₆ alkyl        (i.e., the ring can be aromatic, partially saturated, or        saturated);    -   Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇,        Z₅ is N or CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than        two of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ are N;    -   R₂ is OR_(O), N(R_(N))₂, or SR_(S);    -   R_(O) is H, CN, substituted or unsubstituted alkyl, alkenyl,        alkynyl, aryl, alkanoyl, carbonyloxy, carbonylthio, or        carbonylamino, wherein the alkyl, alkenyl, alkynyl, or alkanoyl        is optionally interrupted by O, S, or NR (in which NR can be        N—C₁-C₆ alkyl), or a phosphate moiety;    -   R_(S) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;    -   each R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;        and    -   R_(3a) is selected from the group consisting of hydrogen,        deuterium, cyano, or C₁-C₆ alkyl;    -   R₃ is selected from the group consisting of deuterium, cyano,        formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl,        alkynyl, haloalkynyl, C₁-C₆ acyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is        directly connected to S), wherein R₁₁ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R₄, R₅, R₆, R₇, R₈, and R₉ are each independently selected from        the group consisting of hydrogen, deuterium, halo, amino,        hydroxy, cyano, formyl, furyl, nitro, alkyl, haloalkyl, alkenyl,        haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is        directly connected to S), wherein R₁₁ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b)        is H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆        acyloxy, amino, or C₁-C₆ acyl, R₂ preferably can be ═O, R₃        preferably can be —OR, wherein R is H or C₁-C₆ alkyl, or    -   R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein        R_(b) and R_(c) are each independently H, C₁-C₆ alkyl, alkoxy        (—O-alkyl), thioalkoxy (—S-alkyl), cyano (—CN), or amino, R₂        preferably can be ═O, R₃ preferably can be —OR, wherein R is H        or C₁-C₆ alkyl, or    -   R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S, R₂        and R₃ preferably can be each independently —OR or —NR_(a)R_(b),        wherein R, R_(a), and R_(b) are each independently H, C₁-C₆        alkyl, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are each independently selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, cyano,        formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl,        alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and        —S(O)_(n)R₁₂ (n=0 to 2, R₁₂ is directly connected to S), wherein        R₁₂ is selected from the group consisting of hydrogen,        deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,        haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy,        alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,        haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,        carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, and        halothiocarbonylthio;    -   wherein the compound is enantiomerically pure at the carbon        substituted with R₂/R₃/R_(3a), and optionally, adjacent R        groups, together, can form a three- to twelve-membered ring.

In some embodiments, the compound has the structure of formula 2a, or apharmaceutically acceptable salt thereof:

wherein:

-   -   X is either O (oxygen) or S (sulfur);    -   Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇,        Z₅ is N or CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than        two of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ are N;    -   R₂ is OR_(O), N(R_(N))₂, or SR_(S);    -   R_(O) is H, CN, substituted or unsubstituted alkyl, alkenyl,        alkynyl, aryl, alkanoyl, carbonyloxy, carbonylthio, or        carbonylamino, wherein the alkyl, alkenyl, alkynyl, or alkanoyl        is optionally interrupted by O, S, or NR (in which NR can be        N—C₁-C₆ alkyl), or a phosphate moiety;    -   R_(S) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;    -   each R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;        and    -   R_(3a) is selected from the group consisting of hydrogen,        deuterium, cyano, or C₁-C₆ alkyl;    -   R₃ is selected from the group consisting of deuterium, cyano,        formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl,        alkynyl, haloalkynyl, C₁-C₆ acyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀ is        directly connected to S), wherein R₁₀ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R₄, R₅, R₆, R₇, R₈, and R₉ are each independently selected from        the group consisting of hydrogen, deuterium, halo, amino,        hydroxy, cyano, formyl, furyl, nitro, alkyl, haloalkyl, alkenyl,        haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is        directly connected to S), wherein R₁₁ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b)        is H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆        acyloxy, amino, or C₁-C₆ acyl, R₂ preferably can be ═O, R₃        preferably can be —OR, wherein R is H or C₁-C₆ alkyl, or    -   R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein        R_(b) and R_(c) are each independently H, C₁-C₆ alkyl, alkoxy        (—O-alkyl), thioalkoxy (—S-alkyl), cyano (—CN), or amino, R₂        preferably can be ═O, R₃ preferably can be —OR, wherein R is H        or C₁-C₆ alkyl, or    -   R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S, R₂        and R₃ preferably can be each independently —OR or —NR_(a)R_(b),        wherein R, R_(a), and R_(b) are each independently H, C₁-C₆        alkyl, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are each independently selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, cyano,        formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl,        alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and        —S(O)_(n)R₁₂ (n=0 to 2, R₁₂ is directly connected to S), wherein        R₁₂ is selected from the group consisting of hydrogen,        deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,        haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy,        alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,        haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,        carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, and        halothiocarbonylthio;    -   wherein the compound is enantiomerically pure at the carbon        substituted with R₂/R₃/R_(3a), and optionally, adjacent R        groups, together, can form a three- to twelve-membered ring.

In some embodiments, the compound has the structure of formula 3, or apharmaceutically acceptable salt thereof:

wherein:

-   -   X₁ is N (nitrogen), O (oxygen), S (sulfur), or C (carbon); X₂ is        N (nitrogen), O (oxygen) S (sulfur), or C (carbon); X₃ is N        (nitrogen), O (oxygen), S (sulfur) or C (carbon); and X₄ is N        (nitrogen) O (oxygen), S (sulfur), or C (carbon), such that at        least one of X₁, X₂, X₃ and X₄ is N, each of X₁, X₂, X₃ and X₄        is optionally selected to form a heteroaromatic, wherein the        bond between X₁ and the adjacent carbon, between X₂ and the        adjacent carbon, between X₁ and X₄, between X₂ and X₃, and        between X₃ and X₄ can be a single bond or a double bond and the        valence of X₁, X₂, X₃ and X₄ is completed with H or C₁-C₆ alkyl        (i.e., the ring can be aromatic, partially saturated, or        saturated);    -   Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇,        Z₅ is N or CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than        two of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ are N;    -   R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b)        is H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆        acyloxy, amino, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein        R_(b) and R_(c) are each independently H, C₁-C₆ alkyl, alkoxy        (—O-alkyl), thioalkoxy (—S-alkyl), cyano (—CN), or amino, or    -   R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S,        wherein R_(a) is H, C₁-C₆ alkyl, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are each independently selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, cyano,        formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl,        alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and        —S(O)_(n)R₁₂ (n=0 to 2, R₁₂ is directly connected to S), wherein        R₁₂ is selected from the group consisting of hydrogen,        deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,        haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy,        alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,        haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,        carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, and        halothiocarbonylthio; and    -   R₂ and R₉ are each independently selected from the group        consisting of hydrogen, aryl, heteroaryl, cycloalkyl,        heterocycloalkyl, alkyl, —NR_(2a)C(O)OR_(2b),        —NR_(2a)C(O)R_(2b), —(C₀-C₆ alkyl)-CONHSO₂R_(2a), —(C₀-C₆        alkyl)-CONHSO₂NR_(2a)R_(2b), —(C₀-C₆ alkyl)-SO₂NHCOR_(2a),        —(C₀-C₆ alkyl)-SO₂NHR_(2a), —C₀-C₆ alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀is directly connected to S), wherein R₁₀ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio, whereinR_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino;wherein the compound is enantiomerically pure in the R₂ or R₉ moiety;

-   -   R₄, R₅, R₆, R₇, and R₈ are each independently selected from the        group consisting of hydrogen, deuterium, halo, amino, hydroxy,        cyano, formyl, furyl, nitro, alkyl, haloalkyl, alkenyl,        haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is        directly connected to S), wherein R₁₁ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;        and    -   optionally, adjacent R groups, together, can form a three- to        twelve-membered ring.

In some embodiments, the compound has the structure of formula 3a, or apharmaceutically acceptable salt thereof:

wherein:

X is either O (oxygen) or S (sulfur);

-   -   Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇,        Z₅ is N or CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than        two of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ are N;    -   R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b)        is H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆        acyloxy, amino, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein        R_(b) and R_(c) are each independently H, C₁-C₆ alkyl, alkoxy        (—O-alkyl), thioalkoxy (—S-alkyl), cyano (—CN), or amino, or    -   R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S,        wherein R_(a) is H, C₁-C₆ alkyl, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are each independently selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, cyano,        formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl,        alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and        —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is directly connected to S), wherein        R₁₁ is selected from the group consisting of hydrogen,        deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,        haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy,        alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,        haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,        carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, and        halothiocarbonylthio; and    -   R₂ and R₉ are each independently selected from the group        consisting of hydrogen, aryl, heteroaryl, cycloalkyl,        heterocycloalkyl, alkyl, —NR_(2a)C(O)OR_(2b),        —NR_(2a)C(O)R_(2b), —(C₀-C₆ alkyl)-CONHSO₂R_(2a), —(C₀-C₆        alkyl)-CONHSO₂NR_(2a)R_(2b), —(C₀-C₆ alkyl)-SO₂NHCOR_(2a),        —(C₀-C₆ alkyl)-SO₂NHR_(2a), —(C₀-C₆ alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀is directly connected to S), wherein R₁₀ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio, whereinR_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino;wherein the compound is enantiomerically pure in the R₂ or R₉ moiety;

-   -   R₄, R₅, R₆, R₇, and R₈ are each independently selected from the        group consisting of hydrogen, deuterium, halo, amino, hydroxy,        cyano, formyl, furyl, nitro, alkyl, haloalkyl, alkenyl,        haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₁ 1 (n=0 to 2, R₁₁ is        directly connected to S), wherein R₁₁ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;        and    -   optionally, adjacent R groups, together, can form a three- to        twelve-membered ring.

In some embodiments, the compound has the structure of formula 3b, or apharmaceutically acceptable salt thereof:

wherein:

-   -   X is either O (oxygen) or S (sulfur);    -   Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇,        Z₅ is N or CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than        two of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ are N;    -   R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b)        is H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆        acyloxy, amino, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein        R_(b) and R_(c) are each independently H, C₁-C₆ alkyl, alkoxy        (—O-alkyl), thioalkoxy (—S-alkyl), cyano (—CN), or amino, or    -   R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S,        wherein R_(a) is H, C₁-C₆ alkyl, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are each independently selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, cyano,        formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl,        alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and        —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is directly connected to S), wherein        R₁₁ is selected from the group consisting of hydrogen,        deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,        haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy,        alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,        haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,        carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, and        halothiocarbonylthio; and    -   R₂ and R₉ are each independently selected from the group        consisting of hydrogen, aryl, heteroaryl, cycloalkyl,        heterocycloalkyl, alkyl, —NR_(2a)C(O)OR_(2b),        —NR_(2a)C(O)R_(2b), —(C₀-C₆ alkyl)-CONHSO₂R_(2a), —(C₀-C₆        alkyl)-CONHSO₂NR_(2a)R_(2b), —(C₀-C₆ alkyl)-SO₂NHCOR_(2a),        —(C₀-C₆ alkyl)-SO₂NHR_(2a), —(C₀-C₆ alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀is directly connected to S), wherein R₁₀ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio, whereinR_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino;wherein the compound is enantiomerically pure in the R₂ or R₉ moiety;

-   -   R₄, R₅, R₆, R₇, and R₈ are each independently selected from the        group consisting of hydrogen, deuterium, halo, amino, hydroxy,        cyano, formyl, furyl, nitro, alkyl, haloalkyl, alkenyl,        haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is        directly connected to S), wherein R₁₁ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;        and    -   optionally, adjacent R groups, together, can form a three- to        twelve-membered ring.

In some embodiments, the compound has the structure of formula 3c, or apharmaceutically acceptable salt thereof:

wherein:

-   -   X₁ is N (nitrogen), O (oxygen), S (sulfur), or C (carbon); X₂ is        N (nitrogen), O (oxygen) S (sulfur), or C (carbon); X₃ is N        (nitrogen), O (oxygen), S (sulfur) or C (carbon); and X₄ is N        (nitrogen) O (oxygen), S (sulfur), or C (carbon), such that at        least one of X₁, X₂, X₃ and X₄ is N, each of X₁, X₂, X₃ and X₄        is optionally selected to form a heteroaromatic, wherein the        bond between X₁ and the adjacent carbon, between X₂ and the        adjacent carbon, between X₁ and X₄, between X₂ and X₃, and        between X₃ and X₄ can be a single bond or a double bond and the        valence of X₁, X₂, X₃ and X₄ is completed with H or C₁-C₆ alkyl        (i.e., the ring can be aromatic, partially saturated, or        saturated);    -   Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇,        Z₅ is N or CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than        two of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ are N;    -   R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b)        is H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆        acyloxy, amino, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein        R_(b) and R_(c) are each independently H, C₁-C₆ alkyl, alkoxy        (—O-alkyl), thioalkoxy (—S-alkyl), cyano (—CN), or amino, or    -   R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S,        wherein R_(a) is H, C₁-C₆ alkyl, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are each independently selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, cyano,        formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl,        alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and        —S(O)_(n)R₁₂ (n=0 to 2, R₁₂ is directly connected to S), wherein        R₁₂ is selected from the group consisting of hydrogen,        deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,        haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy,        alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,        haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,        carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, and        halothiocarbonylthio; and    -   R₂ and R₉ are each independently selected from the group        consisting of hydrogen, aryl, heteroaryl, cycloalkyl,        heterocycloalkyl, alkyl, —NR_(2a)C(O)OR_(2b),        —NR_(2a)C(O)R_(2b), —(C₀-C₆ alkyl)-CONHSO₂R_(2a), —(C₀-C₆        alkyl)-CONHSO₂NR_(2a)R_(2b), —(C₀-C₆ alkyl)-SO₂NHCOR_(2a),        —(C₀-C₆ alkyl)-SO₂NHR_(2a), —(C₀-C₆ alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀is directly connected to S), wherein R₁₀ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio, whereinR_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino;wherein the compound is enantiomerically pure in the R₂ or R₉ moiety;

-   -   R₄, R₅, R₆, R₇, and R₈ are each independently selected from the        group consisting of hydrogen, deuterium, halo, amino, hydroxy,        cyano, formyl, furyl, nitro, alkyl, haloalkyl, alkenyl,        haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is        directly connected to S), wherein R₁₁ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;        and    -   optionally, adjacent R groups, together, can form a three- to        twelve-membered ring.

In still another embodiment, the compound has structural formula 4, or apharmaceutically acceptable salt thereof:

wherein:

-   -   X is O (oxygen) or S (sulfur);    -   Y is a bond, O (oxygen), S (sulfur), or

-   -   Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇,        Z₅ is N or CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than        two of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ are N;    -   R₄, R₅, R₆, R₇, and R₈ are each independently selected from the        group consisting of hydrogen, deuterium, halo, amino, hydroxy,        cyano, formyl, furyl, nitro, alkyl, haloalkyl, alkenyl,        haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is        directly connected to S), wherein R₁₁ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R₂ is OR_(O), N(R_(N))₂, or SR_(S);    -   R_(O) is H, CN, substituted or unsubstituted alkyl, alkenyl,        alkynyl, aryl, alkanoyl, carbonyloxy, carbonylthio, or        carbonylamino, wherein the alkyl, alkenyl, alkynyl, or alkanoyl        is optionally interrupted by O, S, or NR (in which NR can be        N—C₁-C₆ alkyl), or a phosphate moiety;    -   R_(S) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;    -   each R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;    -   R_(3a) is selected from the group consisting of hydrogen,        deuterium, cyano, or C₁-C₆ alkyl;    -   R₃ is selected from the group consisting of deuterium, cyano,        formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl,        alkynyl, haloalkynyl, C₁-C₆ acyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀ is        directly connected to S), wherein R₁₀ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio,    -   wherein the compound is enantiomerically pure at the carbon        substituted with R₂/R₃/R_(3a), and optionally, adjacent R        groups, together, can form a three- to twelve-membered ring.

In some embodiments, the compound has structural formula 5, or apharmaceutically acceptable salt thereof:

wherein:

-   -   X is O (oxygen) or S (sulfur);    -   Y is a bond, O (oxygen), S (sulfur), or

-   -   Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇,        Z₅ is N or CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than        two of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ are N;    -   R₂ and R₉ are each independently selected from the group        consisting of hydrogen, aryl, heteroaryl, cycloalkyl,        heterocycloalkyl, alkyl, —NR_(2a)C(O)OR_(2b),        —NR_(2a)C(O)R_(2b), —(C₀-C₆ alkyl)-CONHSO₂R_(2a), —(C₀-C₆        alkyl)-CONHSO₂NR_(2a)R_(2b), —(C₀-C₆ alkyl)-SO₂NHCOR_(2a),        —(C₀-C₆ alkyl)-SO₂NHR_(2a), —(C₀-C₆ alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀is directly connected to S), wherein R₁₀ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio, whereinR_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino,wherein the compound is enantiomerically pure in the R₂ or R₉ moiety;

-   -   R₄, R₅, R₆, R₇, and R₈ are each independently selected from the        group consisting of hydrogen, deuterium, halo, amino, hydroxy,        cyano, formyl, furyl, nitro, alkyl, haloalkyl, alkenyl,        haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is        directly connected to S), wherein R₁₁ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;        and    -   optionally, adjacent R groups, together, can form a three- to        twelve-membered ring.

In some embodiments, the compound has structural formula 6, or apharmaceutically acceptable salt thereof:

wherein:

-   -   Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇,        Z₅ is N or CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than        two of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ are N;    -   R₁ and R_(1a) are taken together to form ═NR_(b), wherein R_(b)        is H, C₁-C₆ alkyl, hydroxy, C₁-C₆ alkoxy (—O-alkyl), C₁-C₆        acyloxy, amino, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are taken together to form ═CR_(b)R_(c), wherein        R_(b) and R_(c) are each independently H, C₁-C₆ alkyl, alkoxy        (—O-alkyl), thioalkoxy (—S-alkyl), cyano (—CN), or amino, or    -   R₁ and R_(1a) are taken together to form ═O, ═NOR_(a), or ═S,        wherein R_(a) is H, C₁-C₆ alkyl, or C₁-C₆ acyl, or    -   R₁ and R_(1a) are each independently selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, cyano,        formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl,        alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and        —S(O)_(n)R₁₄ (n=0 to 2, R₁₄ is directly connected to S), wherein        R₁₄ is selected from the group consisting of hydrogen,        deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,        haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy,        alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,        haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,        carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, and        halothiocarbonylthio;    -   R₄, R₅, R₆, R₇, and R₈ are each independently selected from the        group consisting of hydrogen, deuterium, halo, amino, hydroxy,        cyano, formyl, furyl, nitro, alkyl, haloalkyl, alkenyl,        haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is        directly connected to S), wherein R₁₁ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;    -   B₁, B₂, B₃, B₄, B₅, and B₆ are each independently C or N;    -   R₉ and R₁₀, the number of which, together, complete the valence        of each of B₁, B₂, B₃, B₄, B₅, and B₆, are each independently        selected from the group consisting of hydrogen, aryl,        heteroaryl, cycloalkyl, heterocycloalkyl, alkyl,        —NR_(2a)C(O)OR_(2b), —NR_(2a)C(O)R_(2b), —(C₀-C₆        alkyl)-CONHSO₂R_(2a), —(C₀-C₆ alkyl)-CONHSO₂NR_(2a)R_(2b),        —(C₀-C₆ alkyl)-SO₂NHCOR_(2a), —(C₀-C₆ alkyl)-SO₂NHR_(2a),        —(C₀-C₆ alkyl)-CONR_(2a)OR_(2b),

deuterium, halo, amino, hydroxy, cyano, formyl, nitro, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio,halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R12 (n=0 to 2, R₁₂is directly connected to S), wherein R₁₂ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and

wherein R_(2a) and R_(2b) are each independently H, C₁-C₆ alkyl, alkoxy(—O-alkyl), hydroxy, thioalkoxy (—S-alkyl), cyano (—CN), or amino,

-   -   R₂ and R₃ are each independently selected from the group        consisting of —NR_(a)R_(b) (R_(a) and R_(b) are each        independently H, C₁-C₆ alkyl, or C₁-C₆ acyl), hydrogen,        deuterium, halo, amino, hydroxy, cyano, formyl, furyl, nitro,        alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,        C₁-C₆ acyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and        —S(O)_(n)R13 (n=0 to 2, R₁₃ is directly connected to S), wherein        R₁₃ is selected from the group consisting of hydrogen,        deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,        haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy,        alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,        haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,        carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, and        halothiocarbonylthio, wherein the compound is enantiomerically        pure in the R₉ or R₁₀ moiety; and    -   optionally, adjacent R groups, together, can form a three- to        twelve-membered ring.

In each of formulae 2, 2a, 3, 3a, 3b, 3c, 4, 5, and 6, in someembodiments, each of R₄, R₅, R₆, and R₇ is hydrogen. In otherembodiments, at least one of R₄, R₅, R₆, and R₇ can be F, C₁, or Br, andthe others of R₄, R₅, R₆, and R₇ are hydrogen. In still otherembodiments, at least two of R₄, R₅, R₆, and R₇, independently, can beF, Cl, or Br, and the others of R₄, R₅, R₆, and R₇ are hydrogen. The F,Cl, or Br can be at the indole ring carbon 5, 6, or 7.

In each of formulae 2a, 3, 3a, 3b, 3c, 4, 5, and 6, in certainembodiments, R₉ can be hydrogen. R₂ can be acyl, cyano,hydroxyl-substituted C₁-C₆ alkyl, amino-substituted C₁-C₆ alkyl, aryl,or heteroaryl. The aryl or heteroaryl can be substituted orunsubstituted. The substituted aryl or heteroaryl can be substitutedwith halo, amino, hydroxyl, or C₁-C₆ alkyl. The amino can beunsubstituted.

In each of formulae 2, 2a, and 4, in certain embodiments, R₂ can be anester. In each of formulae 2, 2a, and 4, in certain embodiments, R₂ canbe hydroxyl or amino and R₃ can be alkyl, aryl, nitro, or cyano. R₉ canbe hydrogen. The amino can be substituted or unsubstituted.

In some embodiments, the compound has a structural formula 8a, 8b, 8c,or 8d, or a pharmaceutically acceptable salt thereof:

wherein R₄, R₅, R₆, and R₇, are each independently selected from thegroup consisting of hydrogen and halo;

-   -   R_(o) is hydrogen, deuterium, alkyl, aryl, or acyl; and    -   R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety.

In one embodiment, R_(o) is H or alkyl. In another embodiment, R_(o) isacyl, for example, a substituted or unsubstituted C₁-C₆ acyl. Thesubstituted or unsubstituted C₁-C₆ acyl can be a substituted C₂, C₃, C₄,C₅, or C₆ acyl, optionally interrupted by O, S, or NR (in which NR canbe N—C₁-C₆ alkyl). The substituent can be a halo, carboxyl, amino,hydroxyl, alkoxy, or phosphonate moiety. The amino moiety can be adialkylamino moiety, for example, dimethylamino, morpholino,methylpiperazinyl, piperazinyl or bipiperidinyl.

In one embodiment of the compound of structural formula 8a or 8b, atleast one of R₄, R₅, R₆, and R₇ is F, Cl, or Br and the others of R₄,R₅, R₆, and R₇ are hydrogen. In another embodiment, at least two of R₄,R₅, R₆, and R₇ are F, Cl, or Br and the others of R₄, R₅, R₆, and R₇ arehydrogen.

In one embodiment, R₅ is F and R₄, R₆, and R₇ are hydrogen. In anotherembodiment, R₆ is F and R₄, R₅, and R₇ are hydrogen. In still anotherembodiment, R₇ is F and R₄, R₅, and R₆ are hydrogen.

In one embodiment, R₅ is Cl and R₄, R₆, and R₇ are hydrogen. In anotherembodiment, R₆ is Cl and R₄, R₅, and R₇ are hydrogen. In still anotherembodiment, R₇ is Cl and R₄, R₅, and R₆ are hydrogen.

In one embodiment, R₅ and R₆ are F and R₄ and R₇ are hydrogen. Inanother embodiment, R₅ and R₇ are F and R₄ and R₆ are hydrogen. In stillanother embodiment, R₆ and R₇ are F and R₄ and R₅ are hydrogen.

In one embodiment, R₅ and R₆ are C₁ and R₄ and R₇ are hydrogen. Inanother embodiment, R₅ and R₇ are C₁ and R₄ and R₆ are hydrogen. Instill another embodiment, R₆ and R₇ are C₁ and R₄ and R₅ are hydrogen.

In some embodiments, each of R₄, R₅, R₆, and R₇ is hydrogen.

In some embodiments, R_(N) can be a phosphate moiety. The phosphatemoiety can have the structure

wherein n can be 0, 1, 2, 3, 4, 5, or 6, R_(x) can be H or C₁-C₆ alkyl,R_(y) can be H or C₁-C₆ alkyl, or, together, R_(x) and R_(y) form aC₃-C₈ cycloalkyl, and Q₁ ⁺ and Q₂ ⁺ can be each, independently, amonocation, or together can be a dication or one of Q₁ ⁺ or Q₂ ⁺ can beC₁-C₆ alkyl, benzyl, allyl or —(CR₂R₃—O)—R₂₃, and each of R₂, R₃ and R₂₃can be, independently, H, or C₁-C₆ alkyl.

In some embodiments, n can be 0 or 1.

In certain circumstances, Q₁ ⁺ and Q₂ ⁺ can be each, independently, analkali metal.

In certain circumstances, Q₁ ⁺ and Q₂ ⁺ can be each, independently,selected from the group consisting of lithium, sodium, potassium,ammonium, alkyl ammonium, and phosphonium.

In certain circumstances, Q₁ ⁺ and Q₂ ⁺ together can be selected fromthe group consisting of an alkaline earth metal salt.

In certain circumstances, Q₁ ⁺ and Q₂ ⁺ can be each independentlyselected from the group consisting of zinc, calcium and magnesium.

Exemplary indole compounds are shown in Table 1 below.

TABLE 1 ARI- # Structural Formula

088

215

092

094

164

165

194

195

200

201

202

203

220

221

209

210

211

212

208

213

214

217

191

178

184

234

075

172

173

232

233

235

179

186

187

218

219

100

223

224

225

226

228

229

192

185

193

196

197

198

199

204

205

207

Single stereochemical isomers, enantiomers, diastereomers, andpharmaceutically acceptable salts of the above exemplified compounds arealso within the scope of the present disclosure. Where appropriate,pharmaceutically acceptable salts may be, for example, derived fromsuitable inorganic and organic acids and bases.

The compound described herein can be isolated as a pharmaceutically purecompound. The compound can be isolated as an oil, crystalline solid or anon-crystalline solid. When enantiomerically pure around the carbonsubstituted with R₂/R₃/R_(3a), the compound can be at least 60%, atleast 70%, at least 80%, at least 85%, at least 90%, at least 95%, atleast 98%, at least 99% or at least 99.5% enantiomeric excess (ee). Theenantiomeric configuration at the carbon substituted with R₂/R₃/R_(3a)can be the (R) configuration. Alternatively, the enantiomericconfiguration at the carbon substituted with R₂/R₃/R_(3a) can be the (S)configuration. The enantiomeric configuration at the carbon substitutedwith R₂/R₃/R_(3a) can be the (+) configuration. Alternatively, theenantiomeric configuration at the carbon substituted with R₂/R₃/R_(3a)can be the (−) configuration.

Where appropriate, acid addition salts can be prepared by reacting thepurified compound in its free-based form, if possible, with a suitableorganic or inorganic acid and isolating the salt thus formed. Examplesof pharmaceutically acceptable acid addition salts include, withoutlimitations, salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid, or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acid.

Where appropriate, base addition salts can be prepared by reacting thepurified compound in its acid form with a suitable organic or inorganicbase and isolating the salt thus formed. Such salts include, withoutlimitations, alkali metal (e.g., sodium, lithium, and potassium),alkaline earth metal (e.g., magnesium and calcium), ammonium and N⁺(C₁₋₄alkyl)₄ salts.

Other pharmaceutically acceptable salts include adipate, alginate,ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate,butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate,lauryl sulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, salicylate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valeratesalts.

In some embodiments, the compound may be selected from ARI-164 orARI-165, or a pharmaceutically acceptable salt thereof.

The indole compounds' activity in stimulating AhR can be measured by,for example, an EROD assay as described below. The EROD assay may beperformed on, e.g., human or mouse hepatocyte cell lines. The indolecompounds of the present disclosure may have an EC₅₀ of about 100 nM orless (e.g., 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less,10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5nM or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, or0.1 nM or less) in a human or mouse EROD assay.

The indole compounds' agonistic effect on AhR's immune-stimulatoryactivity may be measured by the compounds' ability to inhibit IL-21secretion from CD4⁺ T cells, as described below. In such an assay, theindole compounds of the present disclosure may have an IC₅₀ of about 500nM or less (e.g., 400 nM or less, 300 nM or less, 200 nM or less, 100 nMor less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10nM or less, 5 nM or less, 1 nM or less, or 0.1 nM or less).

The PK profiles of the present indole compounds are exemplified in theexamples below. The compounds can have a T_(max) of between 0.05 and 2hours, a C_(max) of between 300 and 50,000 ng/mL, a T_(1/2) of between0.5 and 5 hours, or AUC of between 1,000 and 25,000 hr ng/kg for a 2mg/kg IV dose or 10 mg/kg oral dose.

The indole compounds of the present disclosure may be synthesized bymethods known in the art or by methods illustrated in the examplesbelow.

Synthesis of the phosphate derivatives is described in U.S. ProvisionalApplication No. 62/734,989, filed Sep. 21, 2018, which is incorporatedby reference in its entirety.

The classes of compounds described and claimed herein have been made bythe methods described and have been tested in various in vitroincubations as well as in vivo studies in rat, dog and monkey.

The compounds described herein may contain one or more chiral centers,e.g., ARI-164, ARI-165, ARI-186, ARI-187, and the like. The chiralitymay confer enhanced potency and in vivo as well as in vitro stability tothese compounds. As discussed in detail in the Examples, several chiralalcohol and chiral amines derivatives of the compounds described hereinshowed improved potency as well as reduced susceptibility to cellularoxidation. Further, the improved potency and/or stability of many ofthese chiral compounds was associated with a preferred enantiomericform.

In certain embodiments, the present disclosure refers to a method ofmaking a compound of Structural Formula 9, or an enantiomer,diastereomer, or pharmaceutically acceptable salt thereof:

wherein:

-   -   Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇,        Z₅ is N or CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than        two of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ are N;    -   R₄, R₅, R₆, R₇, R₈, and R₉ are each independently selected from        the group consisting of hydrogen, deuterium, halo, amino,        hydroxy, cyano, formyl, furyl, nitro, alkyl, haloalkyl, alkenyl,        haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁ is        directly connected to S), wherein R₁₁ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R₃ is selected from the group consisting of deuterium, cyano,        formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl,        alkynyl, haloalkynyl, C₁-C₆ acyl, acyloxy, alkoxy, haloalkoxy,        thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,        thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,        halocarbonyloxy, carbonylthio, halocarbonylthio,        thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,        halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀ is        directly connected to S), wherein R₁₀ is selected from the group        consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol,        cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,        haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy,        halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl,        halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,        carbonylthio, halocarbonylthio, thiocarbonyloxy,        halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio;    -   R_(3a) is selected from the group consisting of hydrogen,        deuterium, cyano, or C₁-C₆ alkyl;    -   R_(o) is hydrogen, deuterium, alkyl, aryl, or acyl;    -   each R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl,        carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety;    -   and optionally, adjacent R groups, together, can form a three-        to twelve-membered ring; comprising:    -   (i) contacting a compound of Structural Formula 10 with        (S)-2-methylpropane-2-sulfinamide in the presence of a catalyst        to yield a compound of Structural Formula 11;

-   -   (ii) contacting a compound of Structural Formula 11 with one or        more alkylating agent(s) to yield a compound of Structural        Formula 12;

-   -   (iii) contacting a compound of Structural Formula 12 with a        compound of Structural Formula 13 in the presence of an        organolithium base to yield a compound of Structural Formula 14;

-   -   (iv) subjecting a compound of Structural Formula 14 to acid-base        hydrolysis to obtain a compound of Structural Formula 9.

In particular embodiments, each of R₄, R₅, R₆, R₇, R₈, R₉, and R_(N) ishydrogen.

In particular embodiments, at least one of R₄, R₅, R₆, and R₇ is F, Cl,or Br and the others of R₄, R₅, R₆, and R₇ are hydrogen.

In particular embodiments, R_(o), R₃, and R_(3a) are independently H oralkyl.

In particular embodiments, at least one of Z₁, Z₂, Z₃, Z₄, Z₅, Z₆, or Z₇is N.

In particular embodiments, the compound of Structural formula 9 isenantiomerically pure at the carbon substituted with NHR_(o)/R₃/R_(3a).

In some embodiments, R₃ and R_(3a) together form a three- totwelve-membered ring, including a cyclopropyl, cyclobutyl, cyclopentyl,or cyclohexyl ring.

In some embodiments, the catalyst is a transition metal alkoxide.

In particular embodiments, the transition metal alkoxide is a titaniumalkoxide, such as, for example, titanium isopropoxide.

In some embodiments, the alkylating agent is a metal alkyl, for exampleR_(3a)MgX, alone or in combination with R_(o)X or (R_(o))₂Zn, wherein Xis F, Cl, Br, or I.

In some embodiments, this method can be used to make other compoundsdescribed herein, including compounds of Structural Formulae ARI-179,ARI-186, ARI-187, ARI-218, ARI-219, ARI-226, ARI-232, ARI-233, ARI-234,ARI-235, ARI-236, and the like.

Unless otherwise defined herein, scientific and technical terms used inconnection with the present disclosure shall have the meanings that arecommonly understood by those of ordinary skill in the art. Exemplarymethods and materials are described below, although methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present disclosure. In case ofconflict, the present specification, including definitions, willcontrol. Generally, nomenclature used in connection with, and techniquesof, cell and tissue culture, molecular biology, immunology,microbiology, genetics, analytical chemistry, synthetic organicchemistry, medicinal and pharmaceutical chemistry, and protein andnucleic acid chemistry and hybridization described herein are thosewell-known and commonly used in the art. Enzymatic reactions andpurification techniques are performed according to manufacturer'sspecifications, as commonly accomplished in the art or as describedherein. Further, unless otherwise required by context, singular termsshall include pluralities and plural terms shall include the singular.Throughout this specification and embodiments, the words “have” and“comprise,” or variations such as “has,” “having,” “comprises,” or“comprising,” will be understood to imply the inclusion of a statedinteger or group of integers but not the exclusion of any other integeror group of integers. All publications and other references mentionedherein are incorporated by reference in their entirety. Although anumber of documents are cited herein, this citation does not constitutean admission that any of these documents forms part of the commongeneral knowledge in the art.

In order that this invention may be better understood, the followingexamples are set forth. These examples are for purposes of illustrationonly and are not to be construed as limiting the scope of the inventionin any manner.

Examples Example 1: Preparation of(S)-(6-Fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone(PTC17341-123A, ARI-164) and(R)-(6-Fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone(PTC17341-123B, ARI-165)

Step 1. Preparation of(6-Fluoro-H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone(PTC17341-123, ARI-161)

To an ice-cold suspension of1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propan-1-one (ARI-143;4.0 g, 13.2 mmol) in EtOH/THF (50 mL/50 mL), sodium borohydride (503 mg,13.2 mmol) was added portionwise, and the reaction mixture was stirredfor 1 h. Upon complete consumption of the starting material, as wasindicated by TLC, the mixture was quenched with acetone (2 mL) andconcentrated to remove the organic solvent. The residue was then dilutedwith water (100 mL), followed by extraction with EtOAc (100 mL×4). Thecombined organic phases were washed with brine, dried and concentrated.Trituration of the residue with EtOAc/hexane gave(6-Fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone (3.9g, 97% yield).

Step 2. Preparation of(S)-(6-Fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone(PTC17341-123A, ARI-164) and(R)-1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propyl acetate(Ac-ARI-165)

To a room-temperature solution of(6-Fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone (6.0g, 19.7 mmol) and vinyl acetate (8.5 g, 99 mmol) in acetone (200 mL),Novozym 435 (6.0 g, 10000 PLU/g) was added, and the resulting suspensionwas stirred for 48 h at 25° C. Upon completion, the mixture wasfiltered, and the filtrate was concentrated. Purification of the residueby silica gel column chromatography (hexane/EtOAc=3:1 to 1:1) gave(S)-(6-Fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone(2.3 g, 38% yield) and(R)-1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propyl acetate (2.8g, 41% yield) as yellow solids.

ARI-164: ¹H-NMR (400 MHz, DMSO-d6): δ 12.24 (bs, 1H), 9.11 (s, 1H),8.28˜8.32 (dd, J=5.6 and 9.6 Hz, 1H), 7.83 (s, 1H), 7.37˜7.41 (dd, J=2.4and 9.6 Hz, 1H), 7.11˜7.18 (m, 1H), 5.48 (m, 1H), 4.74 (m, 1H),1.90˜2.00 (m, 1H), 1.75˜1.83 (m, 1H), 0.93 (t, J=7.2 Hz, 3H)

LC-MS: m/z 302.9 [M−H]⁻

Chiral-HPLC purity: 100% (Rt 10.826 min)

Optical Rotation: −39.7° (CH3CN, c=0.310, 20° C.)

Step 3. Preparation of(R)-(6-Fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone(PTC17341-123B, ARI-165)

Lithium hydroxide monohydrate (0.8 g, 19 mmol) was added to an ice-coldsolution of (R)-1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propylacetate (2.0 g, 5.8 mmol) in THF (10 mL) and H₂O (10 mL). The resultingmixture was stirred for 2 h at room temperature, and then acidified with1M HCl aqueous to a pH of 6, followed by extraction with EtOAc (20mL×3). The combined organic phases were washed with brine, dried overNa₂SO₄, filtered and concentrated to dryness. Trituration of the residuewith EtOAc/hexane (1:5, 20 mL), and subsequent filtration and drying,gave(R)-(6-Fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone(1.5 g, 85% yield) as a yellow solid.

ARI-165: 1H-NMR (400 MHz, DMSO-d6): δ 12.25 (bs, 1H), 9.11 (s, 1H),8.28˜8.32 (dd, J=5.6 and 9.6 Hz, 1H), 7.84 (s, 1H), 7.37˜7.41 (dd, J=2.4and 9.6 Hz, 1H), 7.11˜7.18 (m, 1H), 5.46˜5.50 (m, 1H), 4.72˜4.76 (t,J=6.0 Hz, 1H), 1.89˜1.99 (m, 1H), 1.76˜1.85 (m, 1H), 0.92˜0.96 (t, J=7.2Hz, 3H)

LC-MS: m/z 302.9 [M−H]⁻

Chiral-HPLC purity: 97.9% (Rt 13.547 min)

Optical Rotation: +40.3° (CH3CN, c=0.330, 20° C.)

Example 2: Separation of(S)-(6-Fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone(PTC17341-123A, ARI-164) and(R)-(6-Fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone(PTC17341-123B, ARI-165) by SFC

SFC separation of racemic(6-Fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone (4.9g) derived from reduction of1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propan-1-one (ARI-143;5.5 g) gave(S)-(6-Fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone(1.60 g, 100% ee, 33% yield) and(R)-(6-Fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone(1.75 g, 96.7% ee, 37% yield).

Example 3: Preparation of(S)-(4-(1-hydroxypropyl)thiazol-2-yl)(1H-indol-3-yl)methanone(PTC17341-16A, ARI-092) and(R)-(4-(1-hydroxypropyl)thiazol-2-yl)(1H-indol-3-yl)methanone(PTC17341-16A, ARI-094)

Step 1. Preparation of(4-(1-hydroxypropyl)thiazol-2-yl)(1H-indol-3-yl)methanone (PTC17341-16)

To an ice-cold suspension of1-(2-(1H-indole-3-carbonyl)thiazol-4-yl)propan-1-one (ARI-002; 1.4 g, 5mmol) in EtOH/THF (50 mL/50 mL), sodium borohydride (190 mg, 5 mmol) wasadded portionwise, and the mixture was then stirred for 1 h. Uponcomplete consumption of the starting material, as was indicated by TLC,the mixture was quenched with acetone (2 mL) and concentrated to removethe organic solvent. The residue was then diluted with water (100 mL),followed by extraction with EtOAc (100 mL×4). The combined organicphases were washed with brine, dried and concentrated. Purification ofthe residue by silica gel column chromatography (hexane/EtOAc=2:1 to1:1) gave racemic(4-(1-hydroxypropyl)thiazol-2-yl)(1H-indol-3-yl)methanone (690 mg, 49%yield).

Step 2. Chiral Separation of(4-(1-hydroxypropyl)thiazol-2-yl)(1H-indol-3-yl)methanone (PTC17341-16)into (S) (4-(1-hydroxypropyl)thiazol-2-yl)(1H-indol-yl)methanone(PTC17341-16A, ARI-092) and (R)(4-(1-hydroxypropyl)thiazol-2-yl)(1H-indol-3-yl)methanone (PTC17341-16B,ARI-094)

Separation of racemic(4-(1-hydroxypropyl)thiazol-2-yl)(1H-indol-3-yl)methanone (690 mg) bychiral prep-HPLC gave (S)(4-(1-hydroxypropyl)thiazol-2-yl)(1H-indol-yl)methanone (115 mg, 100%ee, 173% yield, Rt 12.138 min) and (R)(4-(1-hydroxypropyl)thiazol-2-yl)(1H-indol-yl)methanone (135 mg, 96.7%ee, 19% yield, Rt 15.243 min).

Example 4: Chiral Synthesis of(S)-(6-Fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone(ARI-164; major product) and(R)-(6-Fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone(ARI-165; minor product)

To an ice-cold solution of1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propan-1-one (150 mg,0.5 mmol) in THF (20 mL), (R)-(+)-2-methyl-CBS-oxazaborolidine (1M intoluene, 0.1 mL, 0.1 mmol) was added, followed by the dropwise additionof BH₃-THF solution (1M, 0.5 mL, 0.5 mmol). The reaction mixture wasstirred for 3 h at 0° C., allowed to warm to room temperature, and thenstirred overnight. The mixture was quenched with acetone (2 mL) andconcentrated to remove the organic solvent. The residue was then dilutedwith water (100 mL), followed by extraction with EtOAc (100 mL×4). Thecombined organic phases were washed with brine, dried and concentrated.Purification of the residue by silica gel column chromatography(hexane/EtOAc=3:1 to 1:1) gave compound(S)-(6-Fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone(50 mg, 34% yield, chiral HPLC purity of 93.5%).

Example 5: Preparation of(S)-(6-Fluoro-1H-indol-3-yl)(4-(1-methoxypropyl)thiazol yl)methanone(PTC17341-138; ARI-184)

To an ice-cold solution of(S)-(6-Fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone(1.0 g, 3.3 mmol) and tetrafluoroboric acid (50% aqueous, 0.1 mL) in THF(50 mL), a freshly prepared diazomethane solution (in ethyl ether, 50mmol) was added dropwise. Upon complete consumption of the startingmaterial, as was indicated by TLC, the reaction mixture was quenchedwith acetic acid (0.5 mL) and then concentrated to remove the organicsolvent. The resulting residue was diluted with water (100 mL), and thenextracted with EtOAc (100 mL×4). The combined organic phases were washedwith brine, dried and concentrated. Purification of the residue bysilica gel column chromatography (hexane/EtOAc=3:1 to 1:1) gave(S)-(6-Fluoro-1H-indol-3-yl)(4-(1-methoxypropyl)thiazol yl)methanone(550 mg, 52% yield) as a yellow solid.

¹H-NMR (400 MHz, DMSO-d6): δ 12.24 (bs, 1H), 9.05 (s, 1H), 8.27˜8.33(dd, J=5.6 and 8.4 Hz, 1H), 7.95 (s, 1H), 7.38˜7.41 (d, J=9.2 Hz, 1H),7.11˜7.18 (m, 1H), 4.40˜4.45 (m, 1H), 3.26 (s, 3H), 1.89˜1.95 (m, 2H),0.86˜0.93 (t, J=7.2 Hz, 3H). DEPT135 (100 MHz, DMSO-d6): δ 138.80,123.00, 122.83, 111.32, 99.65, 99.39, 80.63, 66.79, 28.29, 10.13 LC-MS:m/z 318.9 [M+H]⁺;

Chiral-HPLC purity: 99.8% (Rt 24.148 min)

Example 6: Preparation of(R)-(6-Fluoro-1H-indol-3-yl)(4-(1-methoxypropyl)thiazol-2-yl)methanone(PTC1734-139; ARI-178)

(R)-(6-Fluoro-1H-indol-3-yl)(4-(1-methoxypropyl)thiazol-2-yl)methanone(450 mg, 45% yield) was synthesized according to the method described inExample 5 except that(R)-(6-Fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanonewas used instead of(S)-(6-Fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone.

¹H-NMR (400 MHz, DMSO-d6): δ 12.24 (bs, 1H), 9.04-9.06 (d, J=2.8, 1H),8.27-8.30 (dd, J=6.0 and 8.8 Hz, 1H), 7.95 (s, 1H), 7.38-7.41 (dd, J=2.8and 9.2 Hz, 1H), 7.11-7.18 (m, 1H), 4.40-4.43 (m, 1H), 3.26 (s, 3H),1.89-1.95 (m, 2H), 0.86-0.93 (t, J=7.2 Hz, 3H)

LC-MS: m/z 316.9 [M−H]⁻

(Chiral-HPLC purity: 98.1% (Rt 25.706 min)

Example 7: Preparation of PTC17341-133A(R)-(4-(1-aminopropyl)thiazol-2-yl)(6-fluoro-1H-indol-3-yl)methanone(PTC17341-133A: ARI-187)

Step 1. Preparation of (R)-tert-Butyl 3-(4-(1-(1,3-dioxoisoindolin2-yl)propyl)thiazole-2-carbonyl)-6-fluoro-1H-indole-1-carboxylate (1)

(S)-(6-Fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone(1.6 g, 5 mmol) and Boc₂O (1.2 g, 5.6 mmol) were dissolved in THF (50mL), followed by the addition of DMAP (20 mg, cat.) and TEA (2 mL).After stirring the resulting mixture for 12 at room temperature, it wasdiluted with water (100 mL), and extracted with ethyl acetate (100mL×3). The combined organic layer was then washed with 1N HCl aqueous(100 mL×2) and brine, dried over magnesium sulfate and concentrated toyield Boc-ARI-165 (1.65 g), which was used without further purification.

Next, to an ice-cold solution of triphenylphosphine (1.6 g, 6.4 mmol),compound Boc-ARI-165 (1.65 g, 4 mmol) and phthalimide (0.8 g, 5 mmol) inTHF (40 mL), DIAD (1.2 g, 6 mmol) was added dropwise. After stirring for1 h at 0° C., the reaction mixture was allowed to warm to roomtemperature and further stirred for 16 h. Thereafter, the reactionmixture was concentrated, diluted with ethyl acetate (100 mL), washedwith water (100 mL×2) followed by a 5% solution of sodium bisulphate(100 mL×2), dried and concentrated to dryness. Purification of theresidue by flash chromatography (Hexane/EtOAc=5:1 to 3:1) gave(R)-tert-Butyl3-(4-(1-(1,3-dioxoisoindolin-2-yl)propyl)thiazole-2-carbonyl)-6-fluoro-1H-indole-1-carboxylate(520 mg, 19% yield).

Step 2. Preparation of(R)-(4-(1-aminopropyl)thiazol-2-yl)(6-fluoro-1H-indol-3-yl)methanone(PTC17341-133A: ARI-187)

(R)-tert-Butyl3-(4-(1-(1,3-dioxoisoindolin-2-yl)propyl)thiazole-2-carbonyl)-6-fluoro-1H-indole-1-carboxylate(500 mg, 0.94 mmol) was suspended in hydrazine hydrate (80% solution, 60mL) and EtOH (15 mL), and the resulting mixture was heated under refluxfor 10 h. The reaction mixture was then cooled to room temperature,followed by filtration. The filtrate was concentrated to dryness, andtrituration of the residue with EtOAc/hexane gave compound(R)-(4-(1-aminopropyl)thiazol-2-yl)(6-fluoro-1H-indol-3-yl)methanone(160 mg, 56% yield) as a yellow solid.

¹H-NMR (400 MHz, DMSO-d6): δ 9.15 (s, 1H), 8.26-8.33 (dd, J=5.6 and 8.4Hz, 1H), 7.86 (s, 1H), 7.34-7.39 (dd, J=2.4 and 9.6 Hz, 1H), 7.11-7.17(m, 1H), 4.02-4.06 (t, J=6.4 Hz, 2H), 1.82-1.95 (m, 1H), 1.70-1.80 (m,1H), 0.88-0.93 (t, J=7.2 Hz, 3H)

LC-MS: m/z 303.9 [M+H]⁺;

Chiral-HPLC purity: 100% (Rt 12.890 min).

Example 8: Preparation of(S)-(4-(1-aminopropyl)thiazol-2-yl)(6-fluoro-1H-indol-3-yl)methanone(PTC17341-133B; ARI-186)

Step 1. Preparation of (S)-tert-butyl3-(4-(1-(1,3-dioxoisoindolin-2-yl)propyl)thiazole-2-carbonyl)-6-fluoro-1H-indole-1-carboxylate(2)

(S)-tert-Butyl3-(4-(1-(1,3-dioxoisoindolin-2-yl)propyl)thiazole-2-carbonyl)-6-fluoro-1H-indole-1-carboxylatewas synthesized according to the method described in Step 1 of Example7, except that(R)-(6-Fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanonewas used instead of(S)-(6-Fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone.

Step 2. Preparation of(S)-(4-(1-aminopropyl)thiazol-2-yl)(6-fluoro-1H-indol-3-yl)methanone(PTC17341-133B)

(S)-(4-(1-Aminopropyl)thiazol-2-yl)(6-fluoro-1H-indol-3-yl)methanone(410 mg, 78% yield) was synthesized according to the method described inStep. 3 of Example 7, except that (S)-tert-Butyl3-(4-(1-(1,3-dioxoisoindolin-2-yl)propyl)thiazole-2-carbonyl)-6-fluoro-1H-indole-1-carboxylatewas used instead of (R)-tert-Butyl3-(4-(1-(1,3-dioxoisoindolin-2-yl)propyl)thiazole-2-carbonyl)-6-fluoro-1H-indole-1-carboxylate.

¹H-NMR (400 MHz, DMSO-d6): δ 9.11 (s, 1H), 8.25˜8.30 (dd, J=5.6 and 8.8Hz, 1H), 7.90 (s, 1H), 7.34˜7.38 (dd, J=2.4 and 9.6 Hz, 1H), 7.08˜7.14(m, 1H), 3.94˜3.99 (t, J=6.4 Hz, 2H), 1.82˜2.00 (m, 1H), 1.68˜1.74 (m,1H), 0.83˜0.93 (t, J=7.2 Hz, 3H); LC-MS: m/z 304.0 [M+H]⁺

Chiral-HPLC purity: 100% (Rt 11.890 min)

Example 9: Preparation of(S)-1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propyl4-morpholinobutanoate hydrochloride (ARI-197)

To an ice-cold solution of(S)-(6-fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone(4.09 g, 13.44 mmol) in THF (67.2 mL) and pyridine (6.52 mL, 81 mmol),4-bromobutanoyl chloride (1.968 mL, 16.13 mmol) was added dropwise over5-10 minutes with a syringe. After 5 min, the cold bath was removed andthe reaction was allowed to slowly warm to ambient temperature. Uponcompletion, as was determined by LC-MS (ESI-MS: m/z 453/455 [M+H]⁺), thereaction mixture was concentrated under reduced pressure with no heat,followed by partitioning between EtOAc and a saturated aqueous solutionof NaHCO₃. The organic phase was washed with brine, dried over Na₂SO₄,filtered, and concentrated to a yellow solid. The solid wasco-evaporated with two portions of toluene, briefly placed on the highvacuum, and then used without further purification.

To a solution of the crude(S)-1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propyl4-bromobutanoate (13.44 mmol) in DMF (25 mL), morpholine (7.05 mL, 81mmol) was added. Upon completion of the reaction, as was determined byLC-MS (ESI-MS: m/z 460 [M+H]⁺), the reaction mixture was poured into asaturated aqueous solution of NaHCO₃ and then extracted with EtOAc. Theorganic phase was washed with water followed by brine, dried overNa₂SO₄, and filtered. Celite was added to the filtrate and the mixturewas concentrated to dryness. Chromatographic separation (330 g silicagel, CH₂Cl₂ to 40% 80:18:2 CH₂Cl₂:MeOH:NH₄OH) yielded the amine freebase (S)-1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propyl4-morpholinobutanoate as a yellow solid. The solid was placed on thehigh vacuum for several hours and then dissolved in CH₂Cl₂ (50 mL). Tothis solution, a slight excess of HCl (4N in dioxane; 3.70 mL, 14.78mmol) (confirmed acidic by pH paper) was added with stirring. Thereaction mixture was concentrated under reduced pressure to dryness togive a yellow solid. A smaller batch (3.29 mmol) of the free basepreviously prepared by the same procedure was combined at this point.The combined batch was dissolved in water and acetonitrile, filteredthrough a 0.2 micron nylon filter, and then lyophilized to give(S)-1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propyl4-morpholinobutanoate hydrochloride (7.53 g, 15.19 mmol) as a paleyellow solid. The overall yield from the alcohol (total of 16.73 mmol)was 90%.

ARI-197: ¹H NMR (500 MHz, DMSO-d6) δ 12.30 (s, 1H), 10.07 (br. s, 1H),9.03 (d, J=3.1 Hz, 1H), 8.29 (dd, J=8.7, 5.7 Hz, 1H), 8.04 (s, 1H), 7.40(dd, J=9.5, 2.3 Hz, 1H), 7.17-7.12 (m, 1H), 5.95 (t, J=6.6 Hz, 1H), 3.94(d, J=12.5 Hz, 2H), 3.68 (t, J=12.4 Hz, 2H), 3.41 (d, J=12.4 Hz, 2H),3.13-3.08 (m, 2H), 3.06-2.97 (m, 2H), 2.56 (app t, 7.07 Hz, 2H),2.15-1.92 (m, 4H), 0.93 (t, J=7.1 Hz, 3H);

¹⁹F NMR (470 MHz, D₂O) δ −118.22;

ESI-MS: m/z 460 [M+H]⁺;

Specific Rotation: −67.8° (CH₃CN, c=0.12, 20° C.).

Example 10: Preparation of(S)-1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propyl4-(4-methylpiperazin-1-yl)butanoate dihydrochloride (ARI-196)

(S)-1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propyl4-(4-methylpiperazin-1-yl)butanoate dihydrochloride (902 mg, 1.65 mmol)was synthesized from(S)-(6-fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone(1.046 g, 3.44 mmol) according to the method described in Example 9,except that 1-methylpiperazine was used instead of morpholine.

ARI-196: ¹H NMR (500 MHz, D₂O) δ 8.68 (s, 1H), 8.15 (dd, J=8.8, 5.5 Hz,1H), 7.83 (s, 1H), 7.28 (dd, J=9.5, 2.1 Hz, 1H), 7.13-7.09 (m, 1H), 5.87(t, J=6.8 Hz, 1H), 3.30 (br m, 9H), 2.96-2.93 (m, 1H), 2.81 (s, 3H),2.50 (app t, J=7.0 Hz, 2H), 2.07-2.01 (m, 2H), 1.94-1.88 (m, 2H), 0.88(t, J=7.4 Hz, 3H);

¹⁹F NMR (470 MHz, D₂O) δ −118.24;

ESI-MS: m/z 473 [M+H]⁺;

Specific Rotation: −63.6° (CH₃CN, c=0.055, 20° C.).

Elemental analysis of C₂₄H₂₉FN₄O₃S.2HCl.1.45 H₂O:

-   -   Theoretical: C-50.43; H-5.98; Cl-12.4; N-9.8.    -   Experimental: C-50.16; H-5.67; Cl-12.56; N-9.68.

Example 11: Preparation of(S)-1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propyl4-(dimethylamino)butanoate hydrochloride (ARI-198)

(S)-1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propyl4-(dimethylamino)butanoate hydrochloride (125 mg, 0.275 mmol, 53% yield)was synthesized from(S)-(6-fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone(0.512 mmol) according to the method described in Example 9, except thatdimethylamine (2M in THF) was used instead of morpholine.

ARI-198: ¹H NMR (500 MHz, D₂O) δ 8.65 (s, 1H), 8.12 (dd, J=8.9, 5.4 Hz,1H), 7.81 (s, 1H), 7.25 (dd, J=11.8, 2.2 Hz, 1H), 7.10-7.06 (m, 1H),5.87 (t, J=7.2 Hz, 1H), 3.02 (dd, J=9.4, 6.8 Hz, 2H), 2.72 (s, 6H), 2.51(dt, J=10.4, 2.8 Hz, 2H), 2.06-2.01 (m, 2H), 1.97-1.91 (m, 2H), 0.88 (t,J=7.4 Hz, 3H); ¹⁹F NMR (470 MHz, D₂O) δ −118.35; ESI-MS: m/z 418 [M+H]⁺.

Example 12: Preparation of((S)-1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propyl4-([1,4′-bipiperidin]-1′-yl)butanoate dihydrochloride (ARI-199)

(S)-1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propyl4-(dimethylamino)butanoate dihydrochloride (204 mg, 0.329 mmol, 96%yield) was synthesized from(S)-(6-fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone(0.493 mmol) according to the method described in Example 9, except that4-piperidinopiperidine was used instead of morpholine.

ARI-199: ¹H NMR (500 MHz, DMSO-d6) δ 12.33 (s, 1H), 10.23 (br. s, 1H),10.11 (br. s, 1H), 9.03 (d, J=3.1 Hz, 1H), 8.29 (dd, J=8.8, 5.7 Hz, 1H),8.04 (s, 1H), 7.40 (dd, J=9.5, 2.4 Hz, 1H), 7.17-7.12 (m, 1H), 5.95 (t,J=6.6 Hz, 1H), 3.61 (d, J=11.0 Hz, 2H), 3.42-3.34 (m, 2H), 3.08-3.01 (m,2H), 2.98-2.85 (m, 4H), 2.59-2.53 (m, 2H), 2.26 (d, J=13.1 Hz, 2H),2.15-1.94 (m, 6H), 1.84-1.65 (m, 5H), 1.46-1.35 (m, 1H), 0.93 (t, J=7.3Hz, 3H);

¹⁹F NMR (470 MHz, DMSO-d6) δ −118.59;

ESI-MS: m/z 541 [M+H]⁺.

Example 13: Preparation of(S)-1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propyl2-morpholinoacetate hydrochloride (ARI-205)

(S)-1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propyl2-morpholinoacetate hydrochloride was synthesized from(S)-(6-fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanoneaccording to the method described in Example 9, except that chloroacetylchloride was used in place of 4-bromobutanoyl chloride.

ARI-205: ¹H NMR (500 MHz, DMSO-d6) δ 12.33 (br. s, 1H), 10.79 (br. s,1H), 9.03 (d, J=3.2 Hz, 1H), 8.29 (dd, J=8.8, 5.6 Hz, 1H), 8.14 (s. 1H),7.44 (dd, J=9.5, 2.2 Hz, 1H), 7.18-7.12 (m, 1H), 6.12-6.02 (m, 1H),4.63-2.94 (Obs. m, 10H, morpholine), 2.21-2.03 (m, 1H), 0.95 (t, J=7.3Hz, 3H);

¹⁹F NMR (470 MHz, DMSO-d6) δ −118.58;

ESI MS m/z 430 [M−H]⁻.

Example 14: Preparation of sodium(S)-5-(1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propoxy)-5-oxopentanoate(ARI-192)

Pyridine (0.12 mL, 1.484 mmol) was added to a mixture of(S)-(6-fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone(105 mg, 0.345 mmol) and glutaric anhydride (39.4 mg, 0.345 mmol), andthe resulting solution was heated to 60° C. Upon completion, thereaction mixture was treated with 1:1 MeOH/H₂O (10 mL), followed byaddition of 1.5 mL of a saturated aqueous solution of NaHCO₃. Next, thesolution was concentrated and using MeOH, the sample was adsorbed ontocelite. Chromatographic separation (100 g C18, 10% CH₃CN/H₂O toCH₃CN+0.1% TFA, dry loaded celite) yielded the product as a pale yellowsolid which was contaminated with TFA. The material was then combinedwith another previous batch (50 mg) which was also contaminated withTFA. The combined material was adsorbed onto celite using MeOH. Furtherchromatographic separation (100 g C18, 10% CH₃CN/H₂O to CH₃CN, dryloaded celite) yielded the product, which was then taken up in 1:1MeOH/H₂O and passed through Dowex 50W×8, 50-100 mesh ion exchange resin(1.5 g, 0.191 mmol) in the Na⁺ form. The residue was concentrated andlyophilized from H₂O/CH₃CN to give sodium(S)-5-(1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propoxy)-5-oxopentanoate(84 mg, 0.191 mmol) as a yellow solid. The overall yield was 24% from0.789 mmol of alcohol.

ARI-192: ¹H NMR (500 MHz, DMSO-d6) δ 12.63 (br. s, 0.5H), 12.08 (br. s,0.5H), 9.04 (s, 1H), 8.27 (dd, J=8.7, 5.6 Hz, 1H), 8.00 (s, 1H), 7.37(dd, J=9.6, 2.2 Hz, 1H), 7.15-7.11 (m, 1H), 5.93 (dd, J=7.4, 5.6 Hz,1H), 2.47-2.44 (obscured m, 2H), 2.23 (app t, J=7.3 Hz, 2H), 2.14-1.95(m, 2H), 1.81-1.75 (m, 2H), 0.93 (t, J=7.3 Hz, 3H);

¹⁹F NMR (470 MHz, D₂O) δ −118.38;

ESI-MS: m/z 419 [M+H]⁺.

Example 15: Preparation of sodium(S)-(4-(1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propoxy)-4-oxobutyl)phosphonate(ARI-193)

Step 1. To an ice-cold suspension of 4-phosphonobutanoic acid (168 mg,0.999 mmol) in CH₂Cl₂ (5 mL), oxalyl chloride (0.338 mL, 4.00 mmol) wasadded followed by addition of 2 drops of DMF. After 3 hrs, bubblingceased and the solvent was evaporated to a solid. The solid wasco-evaporated with toluene, dried under high vacuum, and then useddirectly as is.

Step 2. To an ice-cold solution of(S)-(6-fluoro-1H-indol-3-yl)(4-(1-hydroxypropyl)thiazol-2-yl)methanone(215 mg, 0.706 mmol) in THF (10 mL) and pyridine (0.457 mL, 5.65 mmol),5.67 mL of the reagent prepared in Step 1 (23.25 mg/mL in 3:1 THF:DCM)(132 mg, 0.706 mmol) was added dropwise. Later on, an additional 2 mL ofthe reagent prepared in Step 1 (23.25 mg/mL in 3:1 THF:DCM) was added asLC-MS indicated an incomplete reaction. Upon completion, the reactionmixture was treated with water and the majority of the solvent wasconcentrated under reduced pressure. The residue was then partitionedbetween EtOAc and 1N HCl (aq). Since the organic layer became a thickslurry, it was treated with water followed by brine. The emulsion wasthen filtered using a Buchner funnel and the solid was dried overnighton the filter. The EtOAc layer of the filtrate was concentrated and theresulting residue was recombined with the solid using MeOH. Afteraddition of water and a saturated aqueous solution of NaHCO₃, themixture was adsorbed onto celite and then concentrated to dryness.Chromatographic separation (100 g C18, 10% CH₃CN/H₂O to CH₃CN, dryloaded celite) yielded sodium(S)-(4-(1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propoxy)-4-oxobutyl)phosphonate(143 mg, 0.287 mmol) as a yellow solid after lyophilization from waterand acetonitrile.

ARI-193: ¹H NMR (500 MHz, D₂O) δ 8.61 (s, 1H), 8.14-8.11 (m, 1H), 7.80(s, 1H), 7.30-7.28 (m, 1H), 7.09-7.05 (m, 1H), 5.85 (t, J=6.86 Hz, 1H),2.30 (app t, J=7.6 Hz, 2H), 2.02-1.97 (m, 2H), 1.85-1.76 (m, 2H),1.44-1.37 (m, 2H), 0.87 (t, J=7.3 Hz, 3H););

³¹P NMR (202 MHz, D₂O) δ 21.47;

¹⁹F NMR (470 MHz, D₂O) δ −118.50;

ESI-MS: m/z 453 [M−H]⁻.

Example 16: Preparation of2-(2-(1H-indole-3-carbonyl)thiazol-4-yl)-2-aminoacetonitrile

Step 1: Preparation of tert-butyl3-(4-(amino(cyano)methyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(93-1)

Trimethylsilyl cyanide (0.74 mL, 5.5 mmol) was added to a solution oftert-butyl-3-(4-formylthiazole-2-carbonyl)-1H-indole-1-carboxylate (1.40g, 4 mmol) in THF (5 mL) and NH₃-MeOH (7M solution, 20 mL) at roomtemperature. The mixture was stirred for 2 h and then concentrated todryness to afford compound 93-1 (2.0 g, ˜100% yield), which was used fornext step without further purification.

Step 2: Preparation of2-(2-(1H-indole-3-carbonyl)thiazol-4-yl)-2-aminoacetonitrile (ARI-075)

Compound 93-1 (2.00 g, 5 mmol) was dissolved in TFA/DCM (10 mL/10 mL) at0° C. Then the mixture was allowed to warm to room temperate and stirredfor 2 h. Next, the mixture was concentrated to dryness. The residue wassuspended in saturated aqueous KHCO₃ (50 mL) and EtOAc (50 mL), stirredfor 0.5 h, then filtered to collect the solid. The solid was washed withwater (30 mL×3) and EtOAc (30 mL×3), and then dried to afford compoundARI-075 (680 mg, 43% yield) as a yellow solid.

¹H-NMR (400 MHz, DMSO-d6): δ 12.37 (bs, 1H), 9.17 (s, 1H), 8.31˜8.35 (m,1H), 8.07 (s, 1H), 7.56˜7.59 (d, J=6.0 Hz, 1H), 7.28˜7.33 (m, 2H),5.34˜5.39 (t, J=8.0 Hz, 1H), 3.05˜3.08 (d, J=8.0 Hz, 1H).

LC-MS: m/z 281.0 [M−H]⁻.

Example 17: Preparation of2-amino-2-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)acetonitrile(ARI-173)

2-amino-2-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)acetonitrilewas synthesized according to the method described in Example 16 exceptthattert-butyl-3-(4-formylthiazole-2-carbonyl)-6-fluoro-1H-indole-1-carboxylatewas used instead oftert-butyl-3-(4-formylthiazole-2-carbonyl)-1H-indole-1-carboxylate.

¹H-NMR (400 MHz, DMSO-d6): δ 12.15 (bs, 1H), 9.17 (s, 1H), 8.28-8.32(dd, J=5.6 and 8.8 Hz, 1H), 8.08 (s, 1H), 7.37-7.41 (dd, J=2.0 and 8.8Hz, 1H), 7.12-7.19 (m, 1H), 5.33-5.39 (t, J=8.4 Hz, 1H), 3.06-3.08 (d,J=8.4, 2H).

LC-MS: m/z 298.9 [M−H]⁻.

Example 18: Preparation of(6-fluoro-1H-indol-3-yl)(4-(2-hydroxybutan-2-yl)thiazol-2-yl)methanone(PTC17341-143; ARI-209)

Step 1: Preparation of 2-(thiazol-4-yl)butan-2-ol (143-1)

A solution of 1-(thiazol-4-yl)propan-1-one (3.0 g, 21 mmol) in THF (100mL) was stirred and cooled to −10° C. under N2. Next, MeMgI (3 M inEt₂O, 33 mL, 0.1 mol) was added dropwise at 0-10° C. over 30 min. Themixture was allowed to warm to room temperature and stirred for 2 h, andthen quenched with saturated NH₄Cl aqueous (100 mL). The mixture wasextracted with EtOAc (100 mL×3). The combined organic phases were washedwith brine (100 mL×2), dried, and concentrated to dryness. The residuewas purified by silica gel chromatography (EtOAc/Hexane=1:5) andafforded 2-(thiazol-4-yl)butan-2-ol (1.9 g, 57% yield) as an oil.

Step 2: Preparation of (S)-4-(2-(triethylsilyloxy)butan-2-yl)thiazole(143-2)

Compound 143-1 (1.9 g, 12.08 mmol) was dissolved in DCM (21 ml) andcooled to 0° C. Imidazole (1.33 g, 19.9 mmol) was added followed byaddition of a solution of TES-Cl (2.2 g, 14.6 mmol) in DCM (8 mL)dropwise at 0-20° C. The reaction mixture was stirred overnight at roomtemperature, then washed with water, aqueous 5% KHSO₄ (×3), saturatedaqueous NaHCO₃ (×3), and brine, dried over anhydrous Na₂SO₄ andconcentrated to dryness. The residue was purified by distillation underreduced pressure to afford compound 143-2 (2.5 g, 76% yield) as an oil

Step 3: Preparation of(6-fluoro-1H-indol-3-yl)(4-(2-(triethylsilyloxy)butan-2-yl)thiazol-2-yl)methanone (143-3

A solution of 143-2 (1.45 g, 5.34 mmol) in THF (13 mL) and toluene (13mL) was cooled to −78° C., and sec-BuLi (1.3 M solution in hexane, 5.1mL, 6.6 mmol) was added dropwise at −78° C. over 10 min. The mixture wasstirred for 0.5 h at this temperature, then a solution of compoundtert-butyl 6-fluoro-3-(methoxy(methyl)carbamoyl)-1H-indole-1-carboxylate(2.15 g, 6.68 mmol) in THF (14 mL) was added dropwise over 10 min. Themixture was stirred at −78° C. for 1 h then allowed to warm to 0° C. andquenched with aqueous 10% NH₄Cl. The organic phase was collected andwashed with water (×2), saturated aqueous NaHCO₃ (×2), and brine (×1),dried (Na₂SO₄), filtered and concentrated to dryness. The residue wasdissolved in MeOH, and K₂CO₃ (0.74 g, 5.34 mmol) was added. The mixturewas stirred for 2 h at room temperature. The mixture was filtered, andthe filtrate was concentrated to dryness. The residue was triturated inEtOH to afford compound 143-3 (1.5 g, 65% yield).

Step 4: Preparation of(6-Fluoro-1H-indol-3-yl)(4-(2-hydroxybutan-2-yl)thiazol-2-yl)methanone(PTC17341-143; ARI-209)

Tetrabutylammonium fluoride trihydrate (TBAF, 9.0 g, 28.7 mmol) wasadded to a solution of compound 143-3 (1.5 g, 3.5 mmol) in THF (15 mL)at room temperature. The mixture was stirred for 10 h at roomtemperature and then quenched with H₂O. The mixture was extracted withEtOAc (×3). The organic phase was collected and washed with water (×2),saturated aqueous NaHCO₃ (×2), and brine, dried over Na₂SO₄, filtered,and concentrated to dryness. The residue was recrystallized withEtOH/H₂O (9:1) to afford compound PTC17341-143 (ARI-209; 735 mg, 66%yield) as a yellowish solid.

¹H-NMR (400 MHz, DMSO-d6): δ 12.21 (bs, 1H), 9.09 (s, 1H), 8.28-8.32(dd, J=5.6 and 8.8 Hz, 1H), 7.80 (s, 1H), 7.37-7.40 (dd, J=2.4 and 9.6Hz, 1H), 7.11-7.17 (m, 1H), 5.23 (bs, 1H), 1.81-2.00 (m, 2H), 1.54 (s,3H), 0.75-0.80 (t, J=7.2 Hz, 3H). LC-MS: m/z 341.0 [M+Na]*.

Example 19: Preparation of(6-fluoro-1H-indol-3-yl)(4-(3-hydroxypentan-3-yl)thiazol-2-yl)methanone(PTC17341-142; ARI-210)

(6-fluoro-1H-indol-3-yl)(4-(3-hydroxypentan-3-yl)thiazol-2-yl)methanonewas synthesized according to the method described in Example 18 exceptthat EtMgI was used instead of MeMgI.

¹H-NMR (400 MHz, DMSO-d6): δ 12.19 (bs, 1H), 9.05 (s, 1H), 8.29-8.32(dd, J=5.6 and 8.8 Hz, 1H), 7.78 (s, 1H), 7.37-7.41 (dd, J=2.4 and 8.8Hz, 1H), 7.11-7.18 (m, 1H), 4.97 (bs, 1H), 1.91-2.00 (m, 2H), 1.77-1.87(m, 2H), 0.72-0.77 (m, 6H).

Example 20: Preparation of(1H-indol-3-yl)(4-(2-hydroxypropan-2-yl)thiazol-2-yl)methanone(PTC17341-157; ARI-215)

Step 1: Preparation of thiazole-4-carbonitrile (157-1)

A solution of N-methoxy-N-methylthiazole-4-carboxamide (17.2 g, 0.10mol) in THF (500 mL) was stirred and cooled to −10° C. under N2. Next,MeMgI (3 M in Et₂O, 200 mL, 0.60 mol) was added dropwise at 0-10° C.over 30 min. The mixture was allowed to warm to room temperature andstirred for 2 h, and then quenched with saturated NH₄Cl aqueous (500mL). The mixture was extracted with EtOAc (500 mL×3). The combinedorganic phases were washed with brine (500 mL×2), dried, andconcentrated to dryness. The residue was purified by silica gelchromatography (EtOAc/Hexane=1:5) and afforded compound 157-1 (9.3 g,65% yield) as an oil.

Step 2: Preparation of 4-(2-(triethylsilyloxy)propan-2-yl)thiazole(157-2)

157-1 (9.4 g, 65.6 mmol) was dissolved in DCM (113 ml) and cooled to 0°C. Imidazole (72.0 g, 1.06 mol) was added, and then a solution of TES-Cl(11.9 g, 79 mmol) in DCM (85 mL) was added dropwise at 0˜20° C. Thereaction mixture was stirred overnight at room temperature, then washedwith water, aqueous 5% KHSO₄ (×3), saturated aqueous NaHCO₃ (×3), andbrine, dried over anhydrous Na₂SO₄ and concentrated to dryness. Theresidue was purified by distillation under reduced pressure to affordcompound 157-2 (9.6 g, 57% yield) as an oil.

Step 3: Preparation of(1H-indol-3-yl)(4-(2-(triethylsilyloxy)propan-2-yl)thiazol-2-yl)methanone (157-3)

A solution of 4-(2-(triethylsilyloxy)propan-2-yl)thiazole (7.2 g, 28mmol) in THF (8 mL) and toluene (8 mL) was cooled to −78° C., andsec-BuLi (1.3 M solution in hexane, 28 mL, 36.4 mmol) was added dropwiseat −78° C. over 10 min. The mixture was stirred for 0.5 h at thistemperature, then a solution of tert-butyl3-(methoxy(methyl)carbamoyl)-1H-indole-1-carboxylate (10.65 g, 35 mmol)in THF (100 mL) was added dropwise over 10 min. The mixture was stirredat −78° C. for 1 h and, allowed to warm to 0° C., and quenched withaqueous 10% NH₄Cl. The organic phase was collected and washed with water(×2), saturated aqueous NaHCO₃ (×2), and brine, dried (Na₂SO₄), filteredand concentrated to dryness. The residue was dissolved in MeOH, andK₂CO3 (3.87 g, 28 mmol) was added. The mixture was stirred for 2 h atroom temperature. The mixture was filtered, and the filtrate wasconcentrated to dryness. The residue was triturated in EtOH to affordcompound 157-3 (6.5 g, 58% yield).

Step 4: Preparation of(1H-indol-3-yl)(4-(2-hydroxypropan-2-yl)thiazol-2-yl)methanone(PTC17341-157)

Tetrabutylammonium fluoride trihydrate (TBAF, 9.0 g, 28.7 mmol) wasadded to a solution of compound 157-3 (4.8 g, 11.5 mmol) in THF (50 mL)at room temperature, the mixture was stirred for 10 h at roomtemperature, then quenched with H₂O (100 mL). The mixture was extractedwith EtOAc (100 mL×3). The organic phase was collected and washed withwater (500 mL×2), saturated aqueous NaHCO₃ (100 mL×2), and brine (100mL×1), dried over Na₂SO₄, filtered, and concentrated to dryness. Theresidue was recrystallized with EtOH/H₂O (9:1, 300 mL) to affordcompound PTC17341-157 as a yellowish solid.

¹H-NMR (400 MHz, DMSO-d6): δ 12.21 (bs, 1H), 9.14-9.15 (d, J=3.2 Hz,1H), 8.31-8.34 (dd, J=4.0 and 8.4 Hz, 1H), 7.81 (s, 1H), 7.55-7.59 (m,1H), 7.25-7.32 (m, 1H), 5.39 (bs, 1H), 1.58 (s, 6H).

LC-MS: m/z 287.0 [M+H]⁺.

Example 21: Preparation of(6-fluoro-1H-indol-3-yl)(4-(2-hydroxypropan-2-yl)thiazol-2-yl)methanone(ARI-220)

(6-Fluoro-1H-indol-3-yl)(4-(2-hydroxypropan-2-yl)thiazol-2-yl)methanonewas synthesized according to the method described in Example 20 exceptthat tert-butyl3-(methoxy(methyl)carbamoyl)-6-fluoro-1H-indole-1-carboxylate was usedinstead of tert-butyl3-(methoxy(methyl)carbamoyl)-1H-indole-1-carboxylate.

¹H-NMR (400 MHz, DMSO-d6): δ 12.19 (bs, 1H), 9.12-9.14 (d, J=3.2 Hz,1H), 8.27-8.32 (dd, J=5.6 and 8.8 Hz, 1H), 7.82 (s, 1H), 7.36-7.40 (dd,J=2.4 and 8.8 Hz, 1H), 7.10-7.17 (m, 1H), 5.37 (bs, 1H), 1.18 (s, 6H);LC-MS: m/z 303.1 [M−H]⁻.

Example 22: Preparation of(6-fluoro-1H-indol-3-yl)(4-(1-hydroxycyclopropyl)thiazol-2-yl)methanone(PTC17341-158; ARI-221)

Step 1: Preparation of 1-(Thiazol-4-yl)ethanone (158-1)

A solution of compound N-methoxy-N-methylthiazole-4-carboxamide (110.0g, 0.643 mol) in THF (1 L) was stirred and cooled to −10° C. under N2,MeMgBr (1M) was added dropwise at 0-10° C. over 1 h. The mixture wasstirred for 2 h at this temperature, and then quenched with saturatedNH₄Cl aqueous (500 mL). The mixture was warmed to room temperature, thenextracted with EtOAc (1 L×3). The combined organic phases were washedwith brine (500 mL×2), dried, concentrated to dryness. The residue waspurified by distillation under reduced pressure to afford compound 158-1(12.1 g, 69% yield) as an oil.

Step 2: Preparation of 4-(1-tert-butyldimethylsilyloxy)vinyl)thiazole(158-2)

tert-Butyldimethylsilyl trifluoromethanesulfonate (TBS-OTf, 15 mL, 56.3mmol) was added dropwise to a solution of compound 158-1 (5.5 g, 43.3mmol) and TEA (6.6 g, 65 mmol) in DCM (100 mL) at 0° C. The reactionmixture was stirred overnight at room temperature, then washed withwater (50 mL×1) and brine (50 mL×1), dried over anhydrous Na₂SO₄ andconcentrated to dryness. The residue was purified by silica gelchromatography (EtOAc/Hexane=1:30) and afforded compound 158-2 (6.8 g,65% yield) as an oil.

Step 3: Preparation of4-(1-(tert-butyldimethylsilyloxy)cyclopropyl)thiazole (158-3)

Diethylzinc solution (1.0 M in hexanes, 15.6 mL, 15.6 mmol) was addeddropwise to a solution of compound 158-2 (780 mg, 3.9 mmol) anddiiodomethane (4.2 g, 15.6 mmol) in DCM (100 mL) at 0° C. over 10 min.The solution was stirred for 0.5 h at 0° C., then allowed to warm toroom temperature. The mixture was quenched with sat. aqueous NH₄Cl (50mL) and extracted with DCM (50 mL×3). The combined organic layers werewashed with brine, dried, and concentrated to dryness. The residue waspurified by silica gel chromatography (EtOAc/Hexane=1:20) and affordedcompound 158-3 (350 mg, 45% yield) as an oil.

Step 4: Preparation of(4-(1-(tert-Butyldimethylsilyloxy)cyclopropyl)thiazol-2-yl)(6-fluoro-1H-indol-3-yl)methanone(158-4)

A solution of 158-3 (3.23 g, 12.7 mmol) in THF (44 mL) and toluene (44mL) was cooled to −78° C., and sec-BuLi (1.3 M solution in hexane, 12.1mL, 15.7 mmol) was added dropwise at −78° C. over 10 min. The mixturewas stirred for 0.5 h at this temperature, then a solution of compoundtert-butyl-6-fluoro-3-(methoxy(methyl)carbamoyl)-1H-indole-1-carboxylate(5.1 g, 15.8 mmol) in THF (43 mL) was added dropwise over 10 min. Themixture was stirred at −78° C. for 1 h, then allowed to warm to 0° C.and quenched with aqueous 10% NH₄Cl. The organic phase was collected andwashed with water (×2), saturated aqueous NaHCO₃ (×2), and brine, dried(Na₂SO₄), filtered and concentrated to dryness. The residue wasdissolved in MeOH, and K₂CO₃ (1.75 g, 12.7 mmol) was added. The mixturewas stirred for 2 h at room temperature. The mixture was filtered, andthe filtrate was concentrated to dryness. The residue was triturated inEtOH to afford compound 158-4 (2.9 g, 55% yield) as a yellow solid.

Step 5: Preparation of(6-Fluoro-1H-indol-3-yl)(4-(1-hydroxycyclopropyl)thiazol-2-yl)methanone(PTC17341-158)

Tetrabutylammonium fluoride trihydrate (TBAF, 4.83 g, 17.3 mmol) wasadded to a solution of compound 158-4 (2.88 g, 6.91 mmol) in THF (30 mL)at room temperature, the mixture was stirred for 10 h at roomtemperature, then quenched with H₂O. The mixture was extracted withEtOAc (×3). The organic phase was collected and washed with water (×2),saturated aqueous NaHCO₃ (×2), and brine, dried (Na₂SO₄), filtered andconcentrated to dryness. The residue was recrystallized with EtOH/H₂O(9:1) to afford PTC17341-158 (1.8 g, 86% yield) as a yellow solid.

¹H-NMR (400 MHz, DMSO-d6): δ 12.17 (bs, 1H), 8.92 (s, 1H), 8.26-8.30(dd, J=5.6 and 8.8 Hz, 1H), 7.80 (s, 1H), 7.35-7.39 (dd, J=2.4 and 8.8Hz, 1H), 7.10-7.16 (m, 1H), 6.36 (m, 1H), 1.22-1.30 (m, 2H), 1.18-1.20(m, 2H); LC-MS: m/z 303.1 [M+H]⁺.

Example 23: Preparation of(4-(1-aminocyclopropyl)thiazol-2-yl)(6-fluoro-1H-indol-3-yl)methanone(PTC17341-159; ARI-225)

Step 1: Preparation of thiazole-4-carbonitrile (159-1)

TEA (76 g, 748 mmol) and TFAA (108 g, 512 mmol) were added to asuspension of thiazole-4-carboxylic acid (21.46 g, 166.2 mmol) in DCM(800 mL) at 0° C. The mixture was allowed to warm to room temperatureand stirred for 6 h, then diluted with H₂O and EtOAc. The mixture wasstirred for 0.5h, then filtered to collect the solid. The solid waswashed with water (×3) and EtOAc (×3), dried to afford compound 159-1(15.2 g, 83% yield) as an oil.

Step 2: Preparation of 1-(thiazol-4-yl)cyclopropanamine (159-2)

Titanium (IV) isopropoxide (15.1 mL, 55 mmol) was added to a solution ofcompound 159-1 (5.5 g, 50 mmol) in THF (100 mL) at 0° C. The mixture wasstirred for 15 min, then EtMgBr (2 M Et2O solution, 50 mL, 0.1 mol) wasadded dropwise over 30 min at 0° C. The deep black solution was stirredfor 2 h at room temperature, then BF₃.Et₂O (12.5 mL, 0.1 mol) was addeddropwise and stirred for 15 min. The reaction was quenched with 1 Naqueous HCl (18 mL), stirred for 30 min, then alkalized with 1 N aqueousNaOH to pH of 9. The mixture was extracted with DCM (200 mL×3). Thecombined organic layers were washed with brine, dried, concentrated todryness to afford crude compound 159-2 (3.1 g, 44% yield) as an oil,which was used for next step without further purification.

Step 3: Preparation of N,N-Diallyl-1-(thiazol-4-yl)cyclopropanamine(159-3)

KOH (7.9 g, 142 mmol) and allyl bromide (19.3 g, 142 mmol) were added toa solution of compound 159-2 (3.1 g, 22 mmol) in DMF (20 mL). Thereaction mixture was heated to 60° C. and stirred for 4 h. After cooledto room temperature, the mixture was quenched with H₂O (50 mL),extracted with DCM (50 mL×3). The combined organic layers were washedwith brine, dried, concentrated to dryness. The residue was purified bysilica gel chromatography (EtOAc/Hexane=1:3) and afforded compound 159-3(2.2 g, 45% yield) as an oil.

Step 4: Preparation of(4-(1-(diallylamino)cyclopropyl)thiazol-2-yl)(6-fluoro-1H-indol-3-yl)methanone (159-4)

A solution of compound 159-3 (4.43 g, 20.1 mmol) in THF (65 mL) andtoluene (65 mL) was cooled to −78° C., and sec-BuLi (1.3 M solution inhexane, 19.2 mL, 25 mmol) was added dropwise at −78° C. over 10 min. Themixture was stirred for 0.5 h at this temperature, then a solution ofcompound tert-butyl6-fluoro-3-(methoxy(methyl)carbamoyl)-1H-indole-1-carboxylate (8.1 g,25.1 mmol) in THF (68 mL) was added dropwise over 10 min. The mixturewas stirred at −78° C. for 1 h then allowed to warm to 0° C. andquenched with aqueous 10% NH₄Cl. The organic phase was collected andwashed with water (×2), saturated aqueous NaHCO₃ (×2), and brine, dried(Na₂SO₄), filtered and concentrated to dryness. The residue wasdissolved in MeOH, and K₂CO₃ (2.78 g, 20.1 mmol) was added. The mixturewas stirred for 2 h at room temperature. The mixture was filtered, andthe filtrate was concentrated to dryness. The residue was triturated inEtOH to afford compound 159-4 (3.3 g, 43% yield) as a yellow solid.

Step 5: Preparation of(4-(1-aminocyclopropyl)thiazol-2-yl)(6-fluoro-1H-indol-3-yl)methanone(PTC17341-159)

Pd(PPh₃)₄(0) (1 g) was added to a solution of compound 159-4 (2.0 g, 4.1mmol) in DCM (20 mL). Piperidine (2 drops) and AcOH (20 drops) wereadded, then the mixture was heated under reflux for 5 h under N2. Aftercooled to room temperature, the mixture was concentrated to dryness. Theresidue was purified by silica gel chromatography(EtOAc/DCM/MeOH=10:10:1) and afforded compound PTC17341-159 in the formof a yellow solid (460 mg, 28% yield).

¹H-NMR (400 MHz, DMSO-d6): δ 12.17 (bs, 1H), 8.96 (s, 1H), 8.26-8.29(dd, J=5.6 and 8.8 Hz, 1H), 7.84 (s, 1H), 7.34-7.38 (dd, J=2.4 and 9.6Hz, 1H), 7.09-7.16 (m, 1H), 2.50 (bs, 2H) 1.74-1.78 (m, 2H), 1.05-1.10(m, 2H); LC-MS: m/z 302.0 [M+H]⁺.

Example 24: Preparation of(4-(2-aminopropan-2-yl)thiazol-2-yl)(6-fluoro-1H-indol-3-yl)methanone(PTC17341-161; ARI-226

Step 1: Preparation of(6-Fluoro-1H-indol-3-yl)(4-(2-(triethylsilyloxy)propan-2-yl)thiazol-2-yl)methanone (161-1)

A solution of 4-(2-(triethylsilyloxy)propan-2-yl)thiazole (10.1 g, 39.3mmol) in THF (130 mL) and toluene (130 mL) was cooled to −78° C., andsec-BuLi (1.3 M solution in hexane, 37.4 mL, 48.7 mmol) was addeddropwise at −78° C. over 10 min. The mixture was stirred for 0.5 h atthis temperature, then a solution oftert-butyl-6-fluoro-3-(methoxy(methyl)carbamoyl)-1H-indole-1-carboxylate(15.8 g, 49.1 mmol) in THF (130 mL) was added dropwise over 10 min. Themixture was stirred at −78° C. for 1 h then allowed to warm to 0° C. andquenched with aqueous 10% NH₄Cl. The organic phase was collected andwashed with water (×2), saturated aqueous NaHCO₃(×2), and brine, dried(Na₂SO₄), filtered and concentrated to dryness. The residue wasdissolved in MeOH, and K₂CO₃ (5.4 g, 39.3 mmol) was added. The mixturewas stirred for 2 h at room temperature. The mixture was filtered, andthe filtrate was concentrated to dryness. The residue was triturated inEtOH to afford compound 161-1 (11.0 g, 67% yield) as a yellow solid.

Step 2: Preparation of(6-Fluoro-1H-indol-3-yl)(4-(2-hydroxypropan-2-yl)thiazol-2-yl) methanone(161-2)

Tetrabutylammonium fluoride trihydrate (TBAF, 9.0 g, 28.7 mmol) wasadded to a solution of compound 161-1 (4.8 g, 11.5 mmol) in THF (50 mL)at room temperature, the mixture was stirred for 10 h at roomtemperature, then quenched with H₂O (100 mL). The mixture was extractedwith EtOAc (100 mL×3). The organic phase was collected and washed withwater (500 mL×2), saturated aqueous NaHCO₃ (100 mL×2), and brine (100mL×1), dried (Na₂SO₄), filtered and concentrated to dryness. The residuewas recrystallized with EtOH/H₂O (9:1, 300 mL) to afford 161-2 (4.9 g,90% yield) as a yellow solid.

Step 3: Preparation ofN-(2-(2-(6-Fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propan-2-yl)acetamide (161-3)

A solution of compound 161-2 (3.9 g, 7.5 mmol) in AcOH (40 mL) wascooled to 0° C. Acetonitrile (1 mL) and conc. H₂SO₄ (20 mL) were added,then the mixture was heated to 60° C. and stirred for 5 h under N2.After cooled to room temperature, the mixture was diluted with H₂O (100mL), extracted with EtOAc (100 mL×3). The combined organic layers werewashed with brine, dried, concentrated to dryness. The residue waspurified by silica gel chromatography (EtOAc/DCM/THF=3:3:1) and affordedcompound 161-3 (1.6 g, 62% yield).

Step 4: Preparation of(4-(2-Aminopropan-2-yl)thiazol-2-yl)(6-fluoro-1H-indol-3-yl)methanone(PTC17341-161)

KOH (2.6 g, 46 mmol) was added to solution of compound 161-3 (1.6 g, 4.6mmol) in glycol (50 mL). The mixture was heated to 175° C. and stirredfor 8 h. After cooled to room temperature, the mixture was diluted withH₂O (100 mL), extracted with EtOAc (100 mL×3). The combined organiclayers were washed with brine, dried, concentrated to dryness. Theresidue was purified by silica gel chromatography(EtOAc/DCM/THF/MeOH=3:3:1:1) and afforded compound PTC17341-161 (900 mg,64% yield) as yellow solid.

¹H-NMR (400 MHz, DMSO-d6): δ 9.15 (s, 1H), 8.27-8.32 (dd, J=5.6 and 8.8Hz, 1H), 7.83 (s, 1H), 7.36-7.39 (dd, J=2.4 and 9.6 Hz, 1H), 7.10-7.16(m, 1H), 1.49 (s, 6H); LC-MS: m/z 326.0 [M+Na]*.

Example 25: Preparation of D3-ARI-164 (ARI-217) Step 1: Preparation ofD₃-ARI-143

NaOH (2.65 g, 66 mmol) was added to solution of1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propan-1-one (2.0 g,6.6 mmol) in DMSO-d6 (20 mL) and D20 (3 mL). The mixture was heated to95° C. and stirred for 8 h. After cooled to room temperature, themixture was diluted with H₂O (100 mL). The solid was collected,dissolved in in DMSO-d6 (20 mL) and D20 (3 mL). and NaOH (2.65 g, 66mmol) was added. The mixture was heated to 95° C. and stirred for 8 h.This process was repeated 2-3 times until NMR indicated deuteratedratio >99%. Finally, the solid was collected and washed with EtOAc,dried to afford D3-ARI-143 (1.1 g, 55% yield, deuterated ratio 99% byNMR) as yellow solid.

¹H-NMR (400 MHz, DMSO-d6): δ 12.35 (bs, 1H), 9.15-9.17 (d, J=3.2 Hz,1H), 8.27-8.32 (dd, J=5.6 and 8.4 Hz, 1H), 7.39-7.42 (dd, J=2.4 and 9.6Hz, 1H), 7.13-7.19 (m, 1H), 1.41 (s, 3H); LC-MS: m/z 304.0 [M−H]⁻.

Step 2: Preparation of D₃-ARI-164

Compound D₃-ARI-143 (150 g, 0.50 mol) was dissolved THF (1 L). Themixture was cooled to 0° C., then (R)-(+)-2-methyl-CBS-oxazaborolidine(1M in toluene, 100 mL, 0.1 mol) was added, then BH₃-THF solution (1M,500 mL, 0.5 mol) was added dropwise over 2 h. The mixture was stirredfor 3 h at 0° C., then allowed to warm to room temperature and stirredovernight. Chiral HPLC indicated about 90% D₃-ARI-143 was consumed andgave two isomers (S:R=8:2). The mixture was carefully quenched withaddition of acetone (200 mL), then concentrated to removal the organicsolvent, the residue was dissolved in acetone (2 L), vinyl acetate (500mL and Novozym 435 (100.0 g, 10000 u/g) were added. The resultingsuspension was stirred 48 h at 40° C.

This mixture was filtered to collect Novozym 435 (to be recycled) andthe filtrate was concentrated. The residue was triturated withEtOAc/EtOH to afford D₃-ARI-164 (1.1 g, 50% yield, ee 98.2% by chiralHPLC, deuterated ratio 99% by NMR) as a yellow solid and the motherliquor was further purified by silica gel column chromatography(DCM/EtOAc/THF=3:1:1) to give another batch of D₃-ARI-164 (15.7 g, 10%yield. Two batches gave 80.2 g as 53% yield) and compound Ac-D3-ARI-164(16.3 g, 10% yield).

¹H-NMR (400 MHz, DMSO-d6): δ 12.24-12.25 (d, J=2.0 Hz, 1H), 9.10-9.12(d, J=3.2 Hz, 1H), 8.27-8.32 (dd, J=5.6 and 8.4 Hz, 1H), 7.37-7.41 (dd,J=2.4 and 9.6 Hz, 1H), 7.11-7.17 (m, 1H), 5.47 (bs, 1H), 4.73 (s, 1H),0.91-0.93 (d, J=6.8 Hz, 3H); LC-MS: m/z 306.0 [M−H]⁻.

Example 26: Preparation of(S)-(4-(1-aminopropyl)thiazol-2-yl)(6-fluoro-1H-indol-3-yl)methanone(ARI-186)

Step 1: Preparation of(S,E)-2-methyl-N-(thiazol-4-ylmethylene)propane-2-sulfinamide

In a 20 mL microwave vessel, thiazole-4-carbaldehyde (1.27 g, 11.23mmol) was combined with (S)-2-methylpropane-2-sulfinamide (1.36 g, 11.23mmol), then titanium isopropoxide (6.65 ml, 22.45 mmol) was added. Thevessel was heated in a microwave reactor to 70° C. for 15 min. Uponcompletion, the suspension had completely gone into solution. The cooledreaction mixture and a parallel reaction mixture (previously derivedfrom 18.83 mmol of aldehyde 1) were added to a rapidly stirring solutionof 300 mL of EtOAc and 5 mL of satd NaCl. A fine white ppt resulted thatwas removed by filtration over a celite pad. TLC (EtOAc/heptane) showedthe reaction to be complete. Adsorbed onto celite, and then concentratedto dryness. Chromatography (40 g silica gel, heptane to 80%EtOAc/heptane) gave an off-white solid. The solid was co-evaporated withCH₂Cl₂ and heptane twice, then placed on the high vacuum to give(S,E)-2-methyl-N-(thiazol-4-ylmethylene)propane-2-sulfinamide (5.46 g,25.2 mmol, 84% yield) as an off-white solid.

¹H NMR (500 MHz, CDCl3) δ 8.93 (d, J=2.0 Hz, 1H), 8.74 (s, 1H), 8.02 (d,J=2.0 Hz, 1H), 1.29 (s, 9H);

ESI MS m/z 217 [M+H]⁺.

Step 2: Preparation of(S)-2-methyl-N-(1-(thiazol-4-yl)propyl)propane-2-sulfinamide

To a −78° C. solution of(S,E)-2-methyl-N-(thiazol-4-ylmethylene)propane-2-sulfinamide (511 mg,2.36 mmol) in THF (24 mL) was added ethylmagnesium bromide (1.0 M inTHF) (2.60 mL, 2.60 mmol) dropwise. The solution remained clear andcolorless upon addition. The reaction was allowed to slowly warm to roomtemperature overnight. In the morning, satd NH₄Cl was added. HPLCindicated a 5.69:1 ratio. Also, a minor product formed which wasidentified as the reduction product(S)-2-methyl-N-(thiazol-4-ylmethyl)propane-2-sulfinamide. The reactionwas quenched by addition of saturated NH₄Cl followed by EtOAc. Theaqueous layer was extracted twice with EtOAc. The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated. Chromatography (24 g silica gel, heptane to EtOAc, dryload silica gel) gave the desired product (493 mg, 85%) as a mixture ofdiastereomers by ¹H NMR (5.8:1 diastereomeric ratio) and as a whitesolid after co-evaporation with CH₂Cl₂/heptane. A portion of thismixture was evaluated for crystallization. To the solid sulfinamide (304mg) was added dichloromethane (2 mL) and upon dissolution, heptane (8.00mL) was added. The colorless solution was stirred at room temp under N2with a bleed needle to let the DCM slowly escape. A solid startedforming on the edges. The mixture was briefly sonicated to givesignificant solids. After 1 hr, the solid was isolated by filtration toyield 53.9 mg after vacuum drying. ¹H NMR estimated only 1% of the minordiastereomer was present. A second crop of crystals from theconcentrated filtrate was isolated using a slower crystallizationprocess. Excess CH₂Cl₂ (10 mL) was combined with heptane (25 ml). Thiswas allowed to slowly concentrate by evaporation overnight. Theresulting solid was isolated as white needles (83.4 mg). ¹H NMRestimated only 1% of the minor diastereomer was present. This wascombined with batch 1 to give a 45% overall yield.

Major Diastereomer: ¹H NMR (500 MHz, CDCl₃) δ 8.78 (d, J=2.0 Hz, 1H),7.27 (d, J=2.0 Hz, 1H), 4.43 (app q, J=7.0 Hz, 1H), 3.87 (d, J=7.2 Hz,1H), 1.98 (m, 2H), 1.24 (s, 9H), 0.90 (t, J=7.4 Hz, 3H); ESI MS m/z 247[M+H]⁺; HPLC=4.74 min, C18 Kinetex.

Minor Diastereomer (only distinctly separated signals provide forreference): ¹H NMR (500 MHz, CDCl3) δ 8.79 (d, J=2.0 Hz, 1H), 7.19 (d,J=2.0 Hz, 1H), 4.54 (m, 1H), 3.64 (m, 1H), 1.18 (s, 9H). HPLC=4.47 min,C18 Kinetex.

Step 3: Preparation of(S)—N-((S)-1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propyl)-2-methylpropane-2-sulfinamide

To a −78° C. solution of(S)-2-methyl-N-(1-(thiazol-4-yl)propyl)propane-2-sulfinamide (59.5 mg,0.241 mmol) in 500 uL of THF was added n-butyllithium (1.6 M in hexanes)(0.309 mL, 0.495 mmol) with a gastight syringe. The solution remainedclear for the first 1 eq of BuLi. Upon addition of the second equivalentthe solution turned a pale yellow. The reaction mixture warmed to −40°C. over 40 min. This solution was cannulated dropwise into a −15° C.solution of tert-butyl6-fluoro-3-(methoxy(methyl)carbamoyl)-1H-indole-1-carboxylate (89 mg,0.276 mmol) in THF (0.5 mL). The dianion vessel was rinsed with 500 uLof THF and transferred into the Weinreb vessel via the cannula. Uponaddition of the dianion, the solution turned an emerald green. After ˜15min, the green color became a dull olive green. After another 20 min,the reaction was quenched with satd. NH₄Cl and stirred. Subsequently,0.5 mL of 3 N HCl was added to ensure the Weinreb intermediatecompletely decomposed. The work-up solution eventually went from olivegreen to a yellow/orange color. The mixture was extracted with EtOAc,dried over Na₂SO₄, filtered, and concentrated to give crude(S)—N-((S)-1-(2-(6-fluoro-1H-indole-3-carbonyl)thiazol-4-yl)propyl)-2-methylpropane-2-sulfinamide(assumed 0.241 mmol). LCMS shows both desired Boc product (ESI MS m/z508 [M+H]⁺) and des-Boc product (ESI MS m/z 408 [M+H]⁺). The product wasused without further purification.

Step 4: Preparation of(S)-(4-(1-aminopropyl)thiazol-2-yl)(6-fluoro-1H-indol-3-yl)methanone

To crude tert-butyl3-(4-(1-(((S)-tert-butylsulfinyl)amino)propyl)thiazole-2-carbonyl)-6-fluoro-1H-indole-1-carboxylate(122 mg, 0.241 mmol) was added MeOH (10 ml) followed by HCl (4 M indioxane) (1 ml, 4.00 mmol). LCMS shows mainly sulfinamide deprotection.The reaction was concentrated to dryness. The residue was treated withMeOH and 1 mL of 2 N NaOH was added. The residue adsorbed to celiteusing MeOH then concentrated to dryness. Reverse phase chromatography(30 g C18, 10% H₂O/CH₃CN+0.1% NH₄OH to 50% CH₃CN, dry load) gave a cleanseparation to give(4-(1-aminopropyl)thiazol-2-yl)(6-fluoro-1H-indol-3-yl)methanone (48.2mg, 66%) as a yellow solid after lyophilization.

LCMS showed both desired Boc product (ESI MS m/z 304 [M+H]⁺). Majordiastereomer retention time=4.38 min (ARI-186), OJ-X, 4.6×150 mm, 5micron, 25% MeOH+0.05% DEA/CO2 isocratic, 2.2 mL/min, columntemperature: 35° C., 254 nM uv and mass detection. MinorDiastereomer=4.13 min (ARI-187).

Example 27: Preparation of(S)-(4-(1-aminoethyl)thiazol-2-yl)(6-fluoro-1H-indol-3-yl)methanone(ARI-232)

Step 1: Preparation of(S)-2-methyl-N-((S)-1-(thiazol-4-yl)ethyl)propane-2-sulfinamide

To a −78° C. solution of(S,E)-2-methyl-N-(thiazol-4-ylmethylene)propane-2-sulfinamide (506 mg,2.339 mmol) in CH₂Cl₂ (20 mL) was added methylmagnesium bromide (3.0 Min Et20) (0.858 mL, 2.57 mmol) dropwise. The solution becameincreasingly yellow upon addition with no obvious exotherm. The reactionwas allowed to slowly warm to room temperature overnight. The reactionwas quenched by addition of saturated NH₄Cl. The aqueous layer wasextracted with CH₂Cl₂. The combined organic layers were washed withbrine, dried (Na₂SO₄), filtered and concentrated. ¹H NMR indicates an8:1 ratio of diastereomers. The stereochemistry is tentatively assignedassuming the Grignard behaved similarly to the EtMgBr case.Chromatography (24 g silica gel, heptane to EtOAc, dry load silica gel)gave a poorly shaped elution profile. The fractions were combined. Thesolid (466 mg, 8:1 diastereomeric ratio) was dissolved using CH₂Cl₂ (15mL) then 50 mL of heptane was added. Continuous stirring gave crystals.Needles (396.5 mg, 73% yield) were isolated by filtration. ¹H NMRestimates 3.8% of the minor diastereomer present. The solid (396.5 mg)was dissolved in a minimum of CH₂Cl₂ (˜2 mL) then 8 mL of heptane wasadded. The mixture was stirred. Crystals formed within 5 min. Themixture was briefly sonicated to make the crystals smaller then stirredovernight with the vessel capped. The fine white needles were isolatedby filtration to give(S)-2-methyl-N-((S)-1-(thiazol-4-yl)ethyl)propane-2-sulfinamide (318 mg,58.5% overall yield). ¹H NMR estimated <1% of the minor diastereomer ispresent.

Major Diastereomer: ¹H NMR (500 MHz, DMSO-d₆) δ 9.04 (d, J=2.0 Hz, 1H),7.55 (dd, J=0.9, 2.0 Hz, 1H), 5.61 (d, J=7.5 Hz, 1H), 4.53 (app pentet,J=6.9 Hz, 1H), 1.48 (d, J=6.8 Hz, 3H), 1.12 (s, 9H); ESI MS m/z 233[M+H]*, HPLC=4.09 min, C18 Kinetex;

Minor Diastereomer (only select distinctly separated signals provide forreference): ¹H NMR (500 MHz, CDCl₃) δ 7.47 (dd, J=0.8, 2.0 Hz, 1H), 5.44(d, J=6.6 Hz, 1H); HPLC=3.78 min, C18 Kinetex.

Step 2: Preparation of tert-butyl3-(4-((S)-1-(((S)-tert-butylsulfinyl)amino)ethyl)thiazole-2-carbonyl)-6-fluoro-1H-indole-1-carboxylate

To a −78° C. suspension of(S)-2-methyl-N-(1-(thiazol-4-yl)ethyl)propane-2-sulfinamide (156 mg,0.671 mmol) in 1.5 mL of THF was added n-butyllithium (1.6 M in hexanes)(0.860 mL, 1.376 mmol) with a syringe. The suspension turned pale pinkand fully dissolved after warming to −50° C. This solution wascannulated dropwise into a −35° C. solution of tert-butyl6-fluoro-3-(methoxy(methyl)carbamoyl)-1H-indole-1-carboxylate (238 mg,0.738 mmol) in THF (0.5 mL). The dianion vessel was rinsed with 500 uLof THF and transferred into the Weinreb vessel via the cannula. Uponaddition of the dianion, the solution turned an olive then to an emeraldgreen. After ˜20 min, the green color became a dark olive green (now at−15° C.). After another 20 min, the reaction was quenched with satdNH₄Cl and stirred. Subsequently, 0.5 mL of 3 N HCl was added to ensurethe Weinreb intermediate completely decomposed. The work-up solutioneventually went from olive green to a yellow/orange color. The mixturewas extracted with EtOAc, dried over Na₂SO₄, filtered and concentratedto give crude tert-butyl3-(4-((S)-1-(((S)-tert-butylsulfinyl)amino)ethyl)thiazole-2-carbonyl)-6-fluoro-1H-indole-1-carboxylate(0.671 mmol). LCMS shows both desired Boc product (ESI MS m/z 494[M+H]⁺) and des-Boc product (ESI MS m/z 394 [M+H]⁺). The product wasused without further purification.

Step 3: (S)-(4-(1-aminoeth ythiazol-2-yl)(6-fluoro-1H-indol-3-yl)methanone

To crude tert-butyl3-(4-((S)-1-(((S)-tert-butylsulfinyl)amino)ethyl)thiazole-2-carbonyl)-6-fluoro-1H-indole-1-carboxylate(0.671 mmol) was added MeOH (10 ml) then HCl (4 M in dioxane) (1 ml,4.00 mmol). LCMS shows mainly sulfinamide deprotection. The reaction wasconcentrated to dryness. The residue was treated with MeOH (10 mL) and 1mL of 2 N NaOH was added. Upon completion, the residue adsorbed tocelite using MeOH then concentrated to dryness. Reverse phasechromatography (100 g C18, 10% H₂O/CH₃CN+0.1% NH₄OH to 50% CH₃CN, dryload) and then by normal phase chromatography (24 g silica gel, CH₂Cl₂to 18:2:80 MeOH:NH₄OH:CH₂Cl₂, dry load) gave(S)-(4-(1-aminoethyl)thiazol-2-yl)(6-fluoro-1H-indol-3-yl)methanone (151mg, 78%) as a yellow solid after lyophilization. ¹H NMR (500 MHz,DMSO-d₆) δ 9.13 (s, 1H), 8.28 (dd, J=8.7, 5.6 Hz, 1H), 7.81 (d, J=0.8Hz, 1H), 7.37 (dd, J=9.6, 2.3 Hz, 1H), 7.15-7.10 (m, 1H), 4.22-4.18 (m,1H), 1.43 (d, J=6.7 Hz, 3H); ¹⁹F NMR (470 MHz, DMSO-d₆) δ −118.87; ESIMS m/z 288 [M−H]⁻

Example 28: Preparation of(S)-(6-fluoro-1H-indol-3-yl)(4-(1-(methylamino)ethyl)thiazol-2-yl)methanone(ARI-233)

Step 1: Preparation of tert-butyl3-(4-((S)-1-(((S)-tert-butylsulfinyl)(methyl)amino)ethyl)thiazole-2-carbonyl)-6-fluoro-1H-indole-1-carboxylate

To a −78° C. suspension of(S)-2-methyl-N-(1-(thiazol-4-yl)ethyl)propane-2-sulfinamide (144 mg,0.620 mmol) in 2 mL of THF was added n-butyllithium (1.6 M in hexanes)(0.794 mL, 1.27 mmol) with a syringe. This yellow solution was slowlywarmed to −40° C. over 40 min. The dianion was cannulated dropwise intoa −15° C. solution of tert-butyl6-fluoro-3-(methoxy(methyl)carbamoyl)-1H-indole-1-carboxylate (220 mg,0.682 mmol) in THF (0.5 mL). The dianion vessel was rinsed with 500 uLof THF and transferred into the Weinreb vessel via the cannula. Uponaddition of the dianion, the solution turned an olive then to an emeraldgreen. After ˜15 min, the green color became a dark olive green. Afteranother 20 min, iodomethane (0.039 mL, 0.620 mmol) was added at 0° C.The reaction was allowed to warm to room temperature overnight and thenwas quenched by addition of satd NH₄Cl. The mixture was stirred.Subsequently, 0.5 mL of 3 N HCl was added to ensure the Weinrebintermediate completely decomposed. The work-up solution eventually wentfrom olive green to a yellow/orange color. The mixture was extractedwith EtOAc, dried over Na₂SO₄, filtered and concentrated to give crudetert-butyl3-(4-((S)-1-(((S)-tert-butylsulfinylxmethyl)amino)ethyl)thiazole-2-carbonyl)-6-fluoro-1H-indole-1-carboxylate(0.620 mmol). LCMS shows both desired Boc product (ESI MS m/z 508[M+H]⁺) and des-Boc product (ESI MS m/z 408 [M+H]⁺). The product wasused without further purification.

Step 2: Preparation of(S)-(6-fluoro-1H-indol-3-yl)(4-(1-(methylamino)ethyl)thiazol-2-yl)methanone

To crude tert-butyl3-(4-((S)-1-(((S)-tert-butylsulfinyl)(methyl)amino)ethyl)thiazole-2-carbonyl)-6-fluoro-1H-indole-1-carboxylate(0.621 mmol) was added MeOH (10 ml) followed by HCl (4 M in dioxane) (2ml, 8.00 mmol). LCMS showed mainly sulfinamide deprotection. Thereaction was concentrated to dryness. The residue was treated with MeOH(10 mL) and 2 mL of 2 N NaOH was added. Upon completion (<1 hr), theresidue adsorbed to silica gel using MeOH then concentrated to dryness.Chromatography (40 g silica gel, CH₂Cl₂ to 18:2:80 MeOH:NH₄OH:CH₂Cl₂,dry load) gave(S)-(6-fluoro-1H-indol-3-yl)(4-(1-(methylamino)ethyl)thiazol-2-yl)methanone(68.4 mg, 36%) as a yellow solid after lyophilization from acetonitrileand water.

¹H NMR (500 MHz, DMSO-d₆) δ 12.20 (s, 1H), 9.12 (s, 1H), 8.29 (dd,J=8.7, 5.6 Hz, 1H), 7.81 (s, 1H), 7.37 (dd, J=9.6, 2.3 Hz, 1H),7.15-7.11 (m, 1H), 3.88 (q, J=6.6 Hz, 1H), 2.25 (s, 3H), 1.40 (d, J=6.7Hz, 3H); ¹⁹F NMR (470 MHz, DMSO-d₆) δ −118.86;

ESI MS m/z 302 [M−H]⁻.

Example 29: Preparation of Preparation of(4-(aminomethyl)thiazol-2-yl)(6-fluoro-1H-indol-3-yl)methanone (ARI-234)

Step 1: Preparation of(S)-2-methyl-N-(thiazol-4-ylmethyl)propane-2-sulfinamide

To a solution of(S,E)-2-methyl-N-(thiazol-4-ylmethylene)propane-2-sulfinamide (361 mg,1.669 mmol) in MeOH (20 mL) was added sodium borohydride (126 mg, 3.34mmol). After 1 hr, water (5 mL) was added and combined with crudematerial from a parallel reaction which used 0.328 mmol of(S,E)-2-methyl-N-(thiazol-4-ylmethylene)propane-2-sulfinamide. Afterstirring for 1 hr, the reaction was concentrated to dryness, thenadsorbed onto silica gel using MeOH, and then concentrated to dryness.Chromatography (24 g silica gel, CH₂Cl₂ to 80:18:2 CH₂Cl₂:MeOH:NH₄OH,dry load) gave (S)-2-methyl-N-(thiazol-4-ylmethyl)propane-2-sulfinamide(415 mg, 95%) as a white solid after co-evaporation with CH₂Cl₂/heptane.

¹H NMR (500 MHz, CDCl₃) δ 8.79 (d, J=2.0 Hz, 1H), 7.30 (m, 1H), 4.51(ABq, J=3.1, 14.6 Hz, 2H), 3.74 (bs, 1H), 1.24 (s, 9H);

ESI MS m/z 219 [M+H]⁺.

Step 2: Preparation of tert-butyl(S)-3-(4-(((tert-butylsulfinyl)amino)methylthiazole-2-carbonyl)-6-fluoro-1H-indole-1-carboxylate

To a −78° C. solution of(S)-2-methyl-N-(thiazol-4-ylmethyl)propane-2-sulfinamide (415 mg, 1.901mmol) in 5 mL of THF was added n-butyllithium (1.6 M in hexanes) (2.435mL, 3.90 mmol) with a syringe. The solution turned pale pink and thenyellow. After warming to −40° C. over 40 min, this solution wascannulated dropwise into a −15° C. solution of tert-butyl6-fluoro-3-(methoxy(methyl)carbamoyl)-1H-indole-1-carboxylate (674 mg,2.091 mmol) in THF (3 mL). The dianion vessel was rinsed with 2 mL ofTHF and transferred into the Weinreb vessel via the cannula. Uponaddition of the dianion, the solution turned an olive. After ˜15 min,the reaction turned an orange brown. The reaction was allowed to warm to5° C. over 1 hour, then the reaction was quenched with satd NH₄Cl.Subsequently, 1 mL of 3 N HCl was added to ensure the Weinrebintermediate completely decomposed. The mixture was extracted withEtOAc, dried over Na₂SO₄, filtered and concentrated to give crude crudetert-butyl(S)-3-(4-(((tert-butylsulfinyl)amino)methyl)thiazole-2-carbonyl)-6-fluoro-1H-indole-1-carboxylate(1.901 mmol). LCMS shows both desired Boc product (ESI MS m/z 480[M+H]⁺) and des-Boc product (ESI MS m/z 380 [M+H]⁺). The product wasused without further purification.

Step 3: (4-(aminomethyl)thiazol-2-yl)(6-fluoro-1H-indol-3-yl)methanone

To crude tert-butyl(S)-3-(4-(((tert-butylsulfinyl)amino)methyl)thiazole-2-carbonyl)-6-fluoro-1H-indole-1-carboxylate(1.901 mmol) was added MeOH (10 ml) then HCl (4 M in dioxane) (2 ml,8.00 mmol). LCMS shows mainly sulfinamide deprotection. Upon completion(<1 hr), the reaction was concentrated to dryness. The residue wastreated with MeOH (15 mL) and 4 mL of 2 N NaOH was added. Uponcompletion (<1 hr), the residue adsorbed to silica gel using MeOH thenconcentrated to dryness. Chromatography (40 g silica gel, CH₂Cl₂ to18:2:80 MeOH:NH₄OH:CH₂Cl₂, dry load) gave a yellow solid. The solid wastaken up in hot MeOH then treated with activated carbon. Filtration gave(4-(aminomethyl)thiazol-2-yl)(6-fluoro-1H-indol-3-yl)methanone (404 mg,77%) as a yellow solid after lyophilization from acetonitrile and water.¹H NMR (500 MHz, DMSO-d₆) δ 9.14 (s, 1H), 8.29 (dd, J=8.7, 5.6 Hz, 1H),7.81 (m, 1H), 7.36 (dd, J=9.6, 2.3 Hz, 1H), 7.15-7.10 (m, 1H), 3.95 (d,J=0.9 Hz, 2H); ¹⁹F NMR (470 MHz, DMSO-d₆) δ −118.89;

ESI MS m/z 276 [M+H]⁺.

Example 30: Preparation of(S)-(4-(1-aminopropyl)thiazol-2-yl)(1H-indol-3-yl)methanone (ARI-235)

Step 1: Preparation of(S)-2-methyl-N-((S)-1-(thiazol-4-yl)propyl)propane-2-sulfinamide

A mixture of methylmagnesium bromide (3 M in diethylether) (1.200 ml,3.60 mmol) and diethylzinc (15 wt % in toluene) (1.079 ml, 1.200 mmol)was stirred for 10 min at room temperature, then cooled to −78° C. Thena solution of(S,E)-2-methyl-N-(thiazol-4-ylmethylene)propane-2-sulfinamide (519 mg,2.399 mmol) in THF (15 ml) was added dropwise slowly over 40 min andstirred at −78° C. for another 20 min. Satd NH₄Cl was added and the bathremoved. EtOAc was added and the layers were separated. The aqueouslayer was extracted with EtOAc. The combined organics were washed withbrine, dried (Na₂SO₄), filtered and concentrated to give 581 mg of awhite solid which consists of 5.8:1 ratio of the desired (S,S) to (S:R)product and only 1.7% of the reduced imine (i.e.(S)-2-methyl-N-(thiazol-4-ylmethyl)propane-2-sulfinamide). The crudesolid was dissolved with boiling heptane (50 mL). The heat was removedand the mixture was stirred. A white solid subsequently appeared. Themixture was briefly sonicated and the solid collected by filtration togive 430 mg. ¹H NMR shows predominantly the (S,S) diastereomer plus 1.9%of the (S,R) diastereomer and a trace of(S)-2-methyl-N-(thiazol-4-ylmethyl)propane-2-sulfinamide. A secondcrystallization was effected by treatment of the white solid (430 mg)with boiling heptane (10 mL). The hot solution was allowed to cool toambient temperature. The resulting solids were briefly sonicated thenisolated by vacuum filtration to give(S)-2-methyl-N-((S)-1-(thiazol-4-yl)propyl)propane-2-sulfinamide (399mg, 67% yield) as a white solid. ¹H NMR indicates <1% of the (S, R)diastereomer.

¹H NMR (500 MHz, CDCl₃) δ 8.78 (d, J=2.0 Hz, 1H), 7.27 (d, J=2.0 Hz,1H), 4.43 (app q, J=7.0 Hz, 1H), 3.87 (d, J=7.2 Hz, 1H), 1.98 (m, 2H),1.24 (s, 9H), 0.90 (t, J=7.4 Hz, 3H);

ESI MS m/z 247 [M+H]⁺.

Step 2: Preparation of tert-butyl3-(4-((S)-1-(((S)-tert-butylsulfinyl)amino)propyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate

To a −78° C. suspension of(S)-2-methyl-N-((S)-1-(thiazol-4-yl)propyl)propane-2-sulfinamide (658mg, 2.67 mmol) in 8 mL of THF was added n-butyllithium (1.6 M inhexanes) (3.42 mL, 5.48 mmol) with a syringe. The suspension became ayellow solution and, after warming to −40° C. over 40 min, this solutionwas cannulated dropwise into a −15° C. solution of tert-butyl3-(methoxy(methyl)carbamoyl)-1H-indole-1-carboxylate (895 mg, 2.94 mmol)in THF (3 mL). The dianion vessel was rinsed with 2 mL of THF andtransferred into the Weinreb vessel via the cannula. Upon addition ofthe dianion, the solution turned a green color. After ˜15 min, thereaction turned an orange brown. The reaction was allowed to warm to 5°C. over 1 hour afterwards the reaction was quenched with satd NH₄Cl.Subsequently, 1 mL of 3 N HCl was added to ensure the Weinrebintermediate completely decomposed. The mixture was extracted withEtOAc, dried over Na₂SO₄, filtered and concentrated to give crudetert-butyl3-(4-((S)-1-(((S)-tert-butylsulfinyl)amino)propyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(2.67 mmol). LCMS shows both desired Boc product (ESI MS m/z 490 [M+H]+)and des-Boc product (ESI MS m/z 388 [M−H]⁻). The product was usedwithout further purification.

Step 3: Preparation of(S)-(4-(1-aminopropyl)thiazol-2-yl)(1H-indol-3-yl)methanone

To crude tert-butyl3-(4-((S)-1-(((S)-tert-butylsulfinyl)amino)propyl)thiazole-2-carbonyl)-1H-indole-1-carboxylate(2.67 mmol) was added MeOH (15 ml) then HCl (4 M in dioxane) (3 ml,12.00 mmol). LCMS shows mainly sulfinamide deprotection. Upon completion(<1 hr), the reaction was concentrated to dryness. The residue wastreated with MeOH (15 mL) and 4 mL of 2 N NaOH was added. Uponcompletion, the residue was treated with 3 N HCl until neutral. Thesolvent was concentrated to dryness. Then the crude material wasadsorbed to silica gel using MeOH then concentrated to dryness.Chromatography (40 g silica gel, CH₂Cl₂ to 18:2:80 MeOH:NH₄OH:CH₂Cl₂,dry load) gave(S)-(4-(1-aminopropyl)thiazol-2-yl)(1H-indol-3-yl)methanone a yellowsolid after lyophilization from acetonitrile and water.

¹H NMR (500 MHz, DMSO-d₆) δ 12.18 (bs, 1H), 9.12 (s, 1H), 8.32-8.30 (m,1H), 7.80 (d, J=0.6 Hz, 1H), 7.57-7.55 (m, 1H), 7.29-7.24 (m, 2H), 3.98(app t, J=6.5 Hz, 1H), 2.20 (bs, 2H), 1.90-1.82 (m, 1H), 1.75-1.66 (m,1H), 0.90 (t, J=7.3 Hz, 3H);

ESI MS m/z 284 [M−H]⁻.

Example 31: Preparation of(S)-N-((2-(1H-indole-3-carbonyl)thiazol-4-yl)methyl)-2-methylpropane-2-sulfinamide(ARI-236)

Step 1: Preparation of(S)-N-((2-(1H-indole-3-carbonyl)thiazol-4-yl)methyl)-2-methylpropane-2-sulfinamide

To a −78° C. suspension of(S)-2-methyl-N-(thiazol-4-ylmethyl)propane-2-sulfinamide (298 mg, 1.365mmol) in THF (3900 μl) was added n-butyllithium (1.6 M in hexanes) (1749μl, 2.80 mmol). The suspension became a pale yellow solution and waswarmed to −40° C. over 40 min. Separately,N-methoxy-N-methyl-1H-indole-3-carboxamide (307 mg, 1.501 mmol) in THF(4 mL) at room temperature was treated with sodium hydride (85 mg, 2.125mmol) to give a thick suspension of a grey solid. Cooled this mixture to−40° C. and then the dianion previously prepared above was added bycannula. The reaction mixture was allowed to warm to room temperatureovernight with stirring. A tan solution resulted which was treated withsatd NH₄Cl. EtOAc and 3 N HCl (1 mL) were added and the layers wereseparated. The organic was washed with brine, dried (Na₂SO₄), filteredand concentrated to a solid (1.365 mmol; ESI MS m/z 362 [M+H]⁺). Thecrude was taken as is.

Step 2: Preparation of(4-(aminomethyl)thiazol-2-yl)(1H-indol-3-yl)methanone

To crude(S)-N-((2-(1H-indole-3-carbonyl)thiazol-4-yl)methyl)-2-methylpropane-2-sulfinamide(1.365 mmol) was added MeOH (15 ml) then HCl (4 M in dioxane, 3 ml,12.00 mmol). Upon completion (<1 hr), the reaction was concentrated todryness. The residue was treated with MeOH (15 mL) and satd NaHCO₃ wasadded until neutral. The solvent was concentrated to dryness. Then thecrude material was adsorbed to silica gel using MeOH then concentratedto dryness. Chromatography (25 g silica gel, CH₂Cl₂ to 18:2:80MeOH:NH₄OH:CH₂Cl₂, dry load) gave(4-(aminomethyl)thiazol-2-yl)(1H-indol-3-yl)methanone (231 mg, 65%yield) as a yellow solid after lyophilization from acetonitrile andwater.

¹H NMR (500 MHz, DMSO-d6) δ 12.20 (bs, 1H), 9.14 (s, 1H), 8.32-8.30 (m,1H), 7.80 (s, 1H), 7.57-7.55 (m, 1H), 7.29-7.24 (m, 2H), 3.94 (app d,J=0.9 Hz, 2H), 2.07 (bs, 2H);

ESI MS m/z 258 [M+H]⁺.

Example 32: Preparation of(S)-(4-(1-aminopropyl)thiazol-2-yl)(1H-pyrrolo[2,3-b]pyridin-3-yl)methanone

(S)-(4-(1-aminopropyl)thiazol-2-yl)(1H-pyrrolo[2,3-b]pyridin-3-yl)methanonecan be synthesized from(S)-2-methyl-N-((S)-1-(thiazol-4-yl)propyl)propane-2-sulfinamide andN-methoxy-N-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide according tothe method described in Example 31, except thatN-methoxy-N-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide would be usedinstead of N-methoxy-N-methyl-1H-indole-3-carboxamide.

Example 33: Preparation of(S)-(4-(1-aminopropyl)thiazol-2-yl)(1H-pyrrolo[2,3-c]pyridin-3-yl)methanone

(S)-(4-(1-aminopropyl)thiazol-2-yl)(1H-pyrrolo[2,3-c]pyridin-3-yl)methanonecan be synthesized from(S)-2-methyl-N-((S)-1-(thiazol-4-yl)propyl)propane-2-sulfinamide andN-methoxy-N-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxamide according tothe method described in Example 31, except thatN-methoxy-N-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxamide would be usedinstead of N-methoxy-N-methyl-1H-indole-3-carboxamide.

Example 34: Preparation of(S)-(4-(1-aminopropyl)thiazol-2-yl)(1H-pyrrolo[3,2-c]pyridin-3-yl)methanone

(S)-(4-(1-aminopropyl)thiazol-2-yl)(1H-pyrrolo[3,2-c]pyridin-3-yl)methanonecan be synthesized from(S)-2-methyl-N-((S)-1-(thiazol-4-yl)propyl)propane-2-sulfinamide andN-methoxy-N-methyl-1H-pyrrolo[3,2-c]pyridine-3-carboxamide according tothe method described in Example 31, except thatN-methoxy-N-methyl-1H-pyrrolo[3,2-c]pyridine-3-carboxamide would be usedinstead of N-methoxy-N-methyl-1H-indole-3-carboxamide.

Example 35: Preparation of(S)-(4-(1-aminopropyl)thiazol-2-yl)(1H-pyrrolo[3,2-b]pyridin-3-yl)methanone

(S)-(4-(1-aminopropyl)thiazol-2-yl)(1H-pyrrolo[3,2-b]pyridin-3-yl)methanonecan be synthesized from(S)-2-methyl-N-((S)-1-(thiazol-4-yl)propyl)propane-2-sulfinamide andN-methoxy-N-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide according tothe method described in Example 31, except thatN-methoxy-N-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide would be usedinstead of N-methoxy-N-methyl-1H-indole-3-carboxamide.

Example 36: Preparation of(S)-(4-(1-aminoethyl)thiazol-2-yl)(1H-pyrrolo[2,3-b]pyridin-3-yl)methanone

(S)-(4-(1-aminoethyl)thiazol-2-yl)(1H-pyrrolo[2,3-b]pyridin-3-yl)methanonecan be prepared from(S)-2-methyl-N-(1-(thiazol-4-yl)ethyl)propane-2-sulfinamide andN-methoxy-N-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide according tothe method described in Example 31, except thatN-methoxy-N-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide would be usedinstead of N-methoxy-N-methyl-1H-indole-3-carboxamide.

Example 37: Preparation of(S)-(4-(1-aminoethyl)thiazol-2-yl)(1H-pyrrolo[2,3-c]pyridin-3-yl)methanone

(S)-(4-(1-aminoethyl)thiazol-2-yl)(1H-pyrrolo[2,3-c]pyridin-3-yl)methanonecan be prepared from(S)-2-methyl-N-(1-(thiazol-4-yl)ethyl)propane-2-sulfinamide andN-methoxy-N-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxamide according tothe method described in Example 31, except thatN-methoxy-N-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxamide would be usedinstead of N-methoxy-N-methyl-1H-indole-3-carboxamide.

Example 38: Preparation of(S)-(4-(1-aminoethyl)thiazol-2-yl)(1H-pyrrolo[3,2-c]pyridin-3-yl)methanone

(S)-(4-(1-aminoethyl)thiazol-2-yl)(1H-pyrrolo[3,2-c]pyridin-3-yl)methanonecan be prepared from(S)-2-methyl-N-(1-(thiazol-4-yl)ethyl)propane-2-sulfinamide andN-methoxy-N-methyl-1H-pyrrolo[3,2-c]pyridine-3-carboxamide according tothe method described in Example 31, except thatN-methoxy-N-methyl-1H-pyrrolo[3,2-c]pyridine-3-carboxamide would be usedinstead of N-methoxy-N-methyl-1H-indole-3-carboxamide.

Example 39: Preparation of(S)-(4-(1-aminoethyl)thiazol-2-yl)(1H-pyrrolo[3,2-b]pyridin-3-yl)methanone

(S)-(4-(1-aminoethyl)thiazol-2-yl)(1H-pyrrolo[3,2-b]pyridin-3-yl)methanonecan be prepared from(S)-2-methyl-N-(1-(thiazol-4-yl)ethyl)propane-2-sulfinamide andN-methoxy-N-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide according tothe method described in Example 31, except thatN-methoxy-N-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide would be usedinstead of N-methoxy-N-methyl-1H-indole-3-carboxamide.

Example 40: Preparation of(4-((S)-1-(methylamino)ethyl)thiazol-2-yl)(1H-pyrrolo[2,3-b]pyridin-3-yl)methanone

(S)-2-methyl-N-(1-(thiazol-4-yl)ethyl)propane-2-sulfinamide would bedissolved in dry THF cooled to −20° C. and to it would be added oneequivalent of sodium hydride. The solution would be stirred for 10 minand then to it would be added 1.2 equivalents of methyliodide. Thesolution would be stirred for 2 hours, then evaporated to dryness, andthen redissolved in dry THF and the solution would be filtered under anitrogen atmosphere. The THF solution would then be cooled to −78° C.and to it would be added 1.1 equivalents of n-BuLi. The solution wouldthen be warmed to −40° C. This solution would be added by cannula to thepreformed solution of the sodium salt ofN-methoxy-N-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide in THF heldat −15° (prepared by the addition of 1 equivalent of sodium hydride to aTHF solution of (4-(aminomethyl)thiazol-2-yl)(1H-indol-3-yl)methanone).After warming overnight to room temperature, the solution would beworked up as described in Example 31.

Example 41: Preparation of(4-((S)-1-(methylamino)ethyl)thiazol-2-yl)(1H-pyrrolo[2,3-c]pyridin-3-yl)methanone

(S)-2-methyl-N-(1-(thiazol-4-yl)ethyl)propane-2-sulfinamide would bedissolved in dry THF cooled to −20° C. and to it would be added oneequivalent of sodium hydride. The solution would be stirred for 10 minand then to it would be added 1.2 equivalents of methyliodide. Thesolution would be stirred for 2 hours, then evaporated to dryness, andthen redissolved in dry THF and the solution would be filtered under anitrogen atmosphere. The THF solution would then be cooled to −78° C.and to it would be added 1.1 equivalents of n-BuLi. The solution wouldthen be warmed to −40° C. This solution would be added by cannula to thepreformed solution of the sodium salt ofN-methoxy-N-methyl-1H-pyrrolo[2,3-c]pyridine-3-carboxamide in THF heldat −15° C. (prepared by the addition of 1 equivalent of sodium hydrideto a THF solution of(4-(aminomethyl)thiazol-2-yl)(1H-indol-3-yl)methanone). After warmingovernight to room temperature, the solution would be worked up asdescribed in Example 31.

Example 42: Preparation of(4-((S)-1-(methylamino)ethyl)thiazol-2-yl)(1H-pyrrolo[3,2-c]pyridin-3-yl)methanone

(S)-2-methyl-N-(1-(thiazol-4-yl)ethyl)propane-2-sulfinamide would bedissolved in dry THF cooled to −20° C. and to it would be added oneequivalent of sodium hydride. The solution would be stirred for 10 minand then to it would be added 1.2 equivalents of methyliodide. Thesolution would be stirred for 2 hours, then evaporated to dryness, andthen redissolved in dry THF and the solution would be filtered under anitrogen atmosphere. The THF solution would then be cooled to −78° C.and to it would be added 1.1 equivalents of n-BuLi. The solution wouldthen be warmed to −40° C. This solution would be added by cannula to thepreformed solution of the sodium salt ofN-methoxy-N-methyl-1H-pyrrolo[3.2-c]pyridine-3-carboxamide in THF heldat −15° C. (prepared by the addition of 1 equivalent of sodium hydrideto a THF solution of(4-(aminomethyl)thiazol-2-yl)(1H-indol-3-yl)methanone). After warmingovernight to room temperature, the solution is worked up as described inExample 31.

Example 43: Preparation of(4-((S)-1-(methylamino)ethyl)thiazol-2-yl)(1H-pyrrolo[3,2-b]pyridin-3-yl)methanone

(S)-2-methyl-N-(1-(thiazol-4-yl)ethyl)propane-2-sulfinamide would bedissolved in dry THF cooled to −20° C. and to it would be added oneequivalent of sodium hydride. The solution would be stirred for 10 minand then to it would be added 1.2 equivalents of methyliodide. Thesolution would be stirred for 2 hours, then evaporated to dryness, andthen redissolved in dry THF and the solution would be filtered under anitrogen atmosphere. The THF solution would then be cooled to −78° C.and to it would be added 1.1 equivalents of n-BuLi. The solution wouldthen be warmed to −40° C. This solution would be added by cannula to thepreformed solution of the sodium salt ofN-methoxy-N-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide in THF heldat −15° C. (prepared by the addition of 1 equivalent of sodium hydrideto a THF solution of(4-(aminomethyl)thiazol-2-yl)(1H-indol-3-yl)methanone). After warmingovernight to room temperature, the solution would worked up as describedin Example 31.

Example 44: Stimulation of CYP1A1 in human HepG2 cells

CYP1A1 induction is under the control of the AhR signaling pathway. ThisExample describes an in vitro assay (7-ethoxy-resorufin-O-deethylase(EROD) assay) that evaluated the AhR modulating activities of the indolecompounds described herein. In this assay, the indole compounds wereincubated with human HepG2 cells or mouse Hepa1-6 cells. The activity ofCYP1A1 in the cells was measured by the conversion of substrate7-ethoxyresorufin, with the readout being a fluorescence signalassociated with the conversion product. The EC₅₀ values of the indolecompounds as well as the maximum luminescence induced by them in theassay were determined.

Materials

Human HepG2 cells were obtained from Sigma Aldrich (Catalog85011430-1VL).

Methods

Human HepG2 cells were grown to 60-80% confluency in tissue cultureflasks, lifted with non-enzymatic cell dissociation solution (cellstripper), seeded in a 384-well plate at 5,000 cells per well, treatedwith the test compounds, and incubated for 20 hours overnight at 37° C.The treatment medium was removed and a solution of substrate7-ethoxyresorufin (ETX) was added to initiate the reaction. The platewas incubated at 37° C. for 30 minutes. The reaction was subsequentlyterminated by adding tempered methanol. Fluorescent emission wasmeasured at 590 nm with excitation at 530 nm in a FLEXSTATION IIIinstrument (Molecular Devices).

Results

Table 2 shows the EROD assay data of ARI-001 (ITE), ARI-143, ARI-145,ARI-146, ARI-164, ARI-186, ARI-187, ARI-194, ARI-195, ARI-210, ARI-211,ARI-212, ARI-213, ARI-214, ARI-215, ARI-218, ARI-219, ARI-220, ARI-221,ARI-222, ARI-223, ARI-224, ARI-225, ARI-226, ARI-228, and ARI-229derivatives using human HepG2 cells.

TABLE 2 EROD Assay Data in human HepG2 cells Plate 1 Plate 2 Compound IDEC₅₀ nM EC₉₀ nM Compound ID EC₅₀ nM EC₉₀ nM ARI-186 5.8 7.4 ARI-143 95.2347.1 ARI-187 55.6 152.3 ARI-218 6.3 7.9 ARI-194 409.2 517.4 ARI-219124.1 418.8 ARI-195 289.3 847.3 ARI-220 371.8 475.9 ARI-210 240.5 626.6ARI-221 26.1 34.5 ARI-211 35.9 183.0 ARI-222 32.7 218.2 ARI-212 21.9149.6 ARI-223 22.6 102.6 ARI-213 476.3 671.7 ARI-224 33.7 151.9 ARI-214581.6 2,806.0 ARI-225 46.8 108.7 ARI-215 119.0 135.1 ARI-226 24.6 33.0ARI-145 19.3 80.3 ARI-228 65.6 216.7 ARI-146 52.0 152.7 ARI-229 50.3204.3 ARI-001 (ITE) 4,442.0 13,220.0 ARI-001 (ITE) 28,950.0 457,900.0ARI-164 104.1 133.6 ARI-164 103.7 138.2

The results from the above table show that several chiral alcohols andchiral amines showed potency as well as chiral preference, especially,in human HepG2 cells:

-   -   ARI-186 was 9.5× more potent than ARI-187 by EC₅₀, and 20.5×        more potent by EC₉₀;    -   ARI-186 was 17.8× more potent than ARI-164 by EC₅₀, and 18.0×        more potent by EC₉₀;    -   ARI-224 was 3.1× more potent than ARI-164 by EC₅₀, and 0.90× as        potent by EC₉₀; and    -   ARI-226 was 4.2× more potent than ARI-164 by EC₅₀, and 4.2× more        potent by EC₉₀.

Surprisingly, chiral preference for S vs R was maintained in severalinstances. For example, ARI-186 was more 9.6× more potent than ARI-187by EC₅₀, and 20.6× more potent by EC₉₀. Similarly, ARI-218 was 19.7×more potent than ARI-219 by EC₅₀, and 53× more potent by EC₉₀.

Example 45: Determination of metabolic stability of indole compounds

The liver is an important organ in the body for drug metabolism. ThisExample describes hepatocyte intrinsic clearance assays using both humanand rat hepatocytes to evaluate the metabolic stability of the indolecompounds disclosed herein. The parameters measured include t_(1/2)(half-life), CL_(int) (intrinsic clearance), and E_(H) (hepaticextraction ratio).

Materials

Testosterone (Lot FE111011-01) was obtained from Cerilliant (Round Rock,Tex.). 7-hydroxycoumarin (Lot 11631ED) was obtained from Sigma Aldrich(St. Louis, Mo.). Cryopreserved human hepatocytes pooled from ten donormales (X008001), cryopreserved male IRC/CD-1 mouse hepatocytes(M005052), INVITROGRO HI Medium (incubation), and INVITROGRO HT Medium(thawing) were obtained from Bioreclamation IVT (Baltimore, Md.). Allsolvents were obtained from commercial sources and used without furtherpurification.

Methods Metabolic Stability in Hepatocytes

Each test compound was prepared as a 1 mM stock solution in DMSO. A 2 μMsolution of test compound and positive controls were prepared inINVITROGRO HI Medium (incubation). These solutions were pre-warmed in asterile incubator set to maintain 37° C., 5% CO₂, and 98% humidity.Cryopreserved hepatocytes were prepared at a concentration of 2×10⁶living cells/mL in incubation media and pre-warmed in the incubator. Thecompound solutions and hepatocyte mixtures were then combined at a ratioof 1:1 (v:v). The final volume of the reaction mixture was 750 μL,containing 1 μM test compound (10 μM for 7-hydroxycoumarin) and 1×10⁶cells. The reaction mixture was placed in the incubator on a plateshaker. After 0, 15, 30, 60, 90, and 120 minutes of incubation, 100 μLof reaction mixtures were removed from the incubation plate and mixedwith 150 μL of ice-cold acetonitrile in a designated well of a 96-wellcrash plate. The 96-well crash plate was placed on ice for 15 min, andsamples were centrifuged (3,600 RPM, 10 min, 4° C.) to precipitateprotein. The supernatants were diluted 1:1 (v:v) with water containing0.15 μM verapamil and/or 1 μM tolbutamide (internal standards forpositive and negative modes, respectively) in a 96-well shallowinjection plate. This plate was sealed for LC-MS analysis. Allmeasurements were done in duplicate.

LC-MS Analysis Liquid Chromatography

Column: Waters Atlantis T3 Column, 100 Å, 3 μm, 2.1 mm×50 mm (Part#186003717). Mobile Phase A: Water with 0.1% formic acid. Mobile PhaseB: Acetonitrile with 0.1% formic acid. Flow Rate: 0.7 mL/minute.Gradient Program:

Time (min) % A % B 0.0 90 10 0.4 90 10 1.2 10 90 2.0 10 90 2.1 90 10 3.090 10

Total R₁₁ n Time: 3 minutes. Autosampler: 10 μL injection volume.Autosampler Wash: A: 90% water, 10% acetonitrile; B: 90% acetonitrile,10% water.

Mass Spectrometer

Instrument: AB SCIEX API4000. Interface: Turbo Ionspray. Mode: Q1Multiple Ions. Method: 3.0 minute duration. Mass Spectrometer SourceSettings:

IS TEM CUR GS1 GS2 5500 550 20 50 50

Data and Calculations

Determination of t_(1/2), CL_(int), E_(H), and % R at 60 Minutes

The residual compound remaining (% R) was determined from LC-MS peakareas by comparison to the zero time point. Metabolic half-life(t_(1/2)) and intrinsic clearance (CL_(int)) values were calculated fromthe slope of the plot of In (% R) vs. time and the concentration ofhepatocytes present in the incubation. Percent remaining at 60 minuteswas calculated by plugging in the 60 minute value into the slopeequation generated by the percent remaining time points.

Calculation of In Vivo Hepatic Clearance

In vivo hepatic clearance CL_(H) was calculated using the well stirredliver model according to the following equation:

${{CL_{H}} = \frac{Q_{H} \cdot f_{u} \cdot {CL}_{int}^{\prime}}{Q_{H} + {f_{u} \cdot {CL}_{int}^{\prime}}}},$

where Q_(H) is the total liver blood flow, f_(u) is unbound fraction ofthe drug, and CL′_(int) is defined as follows:

CL′ _(int) =CL _(int)×(10⁶ cells/g of liver weight)×(g liver weight/kgof body weight).

In the first approximation, used in this study, f_(u)=1.

Hepatic extraction ratio E_(H) was calculated using the followingequation:

$E_{H} = \frac{CL_{H}}{Q_{H}}$

Corresponding physiological parameters used in calculations for allspecies are shown below in Table 3.

TABLE 3 Physiological Parameters of Mammalian Species Used forCalculation of CL_(H) g liver wt/kg 10⁶ cells/g Species body wt liver wtQ_(H) (mL/min/kg body wt) Human 26 99 21 Mouse 55 128 120

Results

Table 4 shows the t_(1/2), CL_(int), and E_(H) of various indolecompounds described herein as assayed on human and rat hepatocytes.

TABLE 4 Metabolism of Indole Compounds Human Hepatocytes Rat HepatocytesCL_(int) CL_(int) Compound t_(1/2) (μL/min/ E_(H) t_(1/2) (μL/min/ E_(H)ID (min) 10⁶ ells) (%) (min) 10⁶ cells) (%) Batch 1, Part 1 ARI088 0.912.366 24.1 1.0 11.594 43.7 ARI100 46.1 0.251 1.9 1.3 8.733 36.9 ARI1430.6 18.494 26.1 0.8 13.820 48.0 ARI164 0.7 15.696 25.3 1.5 7.454 33.3ARI186 7.9 1.453 8.7 2.8 4.127 21.6 ARI187 18.6 0.621 4.4 2.3 4.926 24.8ARI194 0.6 20.465 26.5 0.6 18.246 55.0 ARI195 0.6 20.584 26.5 1.3 9.16438.0 Batch 1, Part 2 ARI143 0.7 16.203 25.5 0.8 13.708 47.8 ARI164 0.913.556 24.6 1.5 7.900 34.6 ARI209 0.8 14.727 25.0 0.9 12.167 44.9 ARI2100.7 16.016 25.4 0.4 29.925 66.7 ARI211 1.0 11.349 23.6 3.6 3.208 17.7ARI212 0.3 44.086 28.9 3.0 3.850 20.5 ARI213 0.8 13.989 24.7 0.8 13.88148.1 ARI214 0.5 21.539 26.7 1.4 8.005 34.9 ARI215 0.6 17.944 25.9 0.913.439 47.3 Batch 2, Part 1 ARI143 0.6 18.445 26.1 0.8 14.086 48.5ARI164 0.7 15.446 25.2 1.9 6.042 28.8 ARI001 0.0 767.365 31.3 0.1 89.78685.7 ARI218 1.3 9.165 22.2 1.0 11.067 42.5 ARI219 5.3 2.174 11.5 0.521.417 58.9 ARI220 1.4 8.330 21.6 2.4 4.774 24.2 ARI221 0.5 25.251 27.32.1 5.550 27.1 ARI222 0.4 27.669 27.6 0.7 16.981 53.2 Batch 2, Part 2ARI143 0.7 16.920 25.7 0.8 14.792 49.7 ARI164 0.8 13.712 24.6 1.4 8.05035.0 ARI223 1.0 11.626 23.7 0.5 25.589 63.1 ARI224 3.0 3.850 15.8 1.96.123 29.0 ARI225 2.3 4.965 17.8 0.5 23.158 60.8 ARI226 3.0 3.850 15.81.8 6.540 30.4 ARI227 0.8 13.943 24.7 0.3 42.587 74.0 Batch 2, Part 3ARI 143 0.3 43.661 26.1 0.3 43.829 74.6 ARI 164 0.8 15.383 19.9 0.814.236 48.8 ARI228 0.2 64.371 27.6 0.1 112.145 88.2 ARI229 2.3 5.02811.4 1.0 11.728 43.9

These results indicate that in rats, ARI-186 was found to be extremelylow clearance, with a CL_(int) of 4.1 μl/min/10⁶ cells and a hepaticextraction ratio of 21.6%. This CL_(int) value is 1.8× lower than thatof ARI-164. In humans, AR-186 was also low clearance, with a CL_(int) of1.5 μl/min/10⁶ cells and 8.7% hepatic extraction ratio. This CL_(int)value is 10.8× lower than that of ARI-164. ARI-224 and ARI-226 hadvalues slightly lower than ARI-164 in rats. In human cells, however,both compounds had at least a 4× improvement in CL_(int) compared toARI-164.

Example 46: CYP Profiling of Indole Compounds

In order to investigate the contributions of CYP1A2 and CYP3A4 to themetabolism of the compounds of the present disclosure, human livermicrosomes were incubated with the test compounds for 30 minutes in thepresence of selective chemical inhibitors furafylline (1A2) andketoconazole (3A4).

Results:

Table 5 shows the metabolic turnover rate of the tested compounds.

TABLE 5 CYP Profiling of indole compounds % Compound % Inhibition HLMsMetabolized at 30 min Relative to Compound No CYP1A2 CYP3A4 NegativeControl ID Inhibitor Inhibitor Inhibitor 1A2 3A4 Batch 1 Phenacitin 31% 1% — 97% N/A Midazolam 97% —  0% N/A 100%  ARI-100  2%  0%  8% 100% None ARI-143 69% 32% 82% 54% None ARI-186 13% 10% 12% 23%  8% ARI-187 4%  7%  3% None 25% ARI-211 50% 67% 59% None None ARI-212 43% 51% 24%None 44% Batch 2 Phenacitin 36%  3% 23% 92% 36% Midazolam 98% 96%  1% 2% 99% ARI-143 91% 17% 92% 81% None ARI-164 37%  4% 34% 89%  8% ARI-21816% 17%  0% None 100%  ARI-219 13%  5% 23% 62% None ARI-220 41%  0% 27%100%  34% ARI-221 95% 28% 82% 71% 14% ARI-223 79% 12% 42% 85% 47%ARI-224  9%  7%  8% 22% 11% ARI-225 39% 10% 29% 74% 26% ARI-226  6% 16%11% None None ARI-228 89% 23% 75% 74% 16% ARI-229  0%  0%  0% None None

Confirming prior studies, ARI-164 was shown to have metabolic turnoverin 30 minutes, with 37% metabolized. In the presence of furafylline,only 4% of ARI-164 was metabolized, demonstrating 89% inhibition by a1A2 inhibitor. However, in the presence of ketoconazole, there was onlyan 8% inhibitory effect. Thus, ARI-164 is selectively metabolized byCYP1A2.

ARI-186 was shown to be a very low turnover compound, with only 13%metabolized in 30 minutes. Importantly, neither furafylline norketoconazole had much effect on ARI-186 metabolism.

ARI-224 and ARI-226 similarly were low turnover, with little to noimpact on metabolism in the presence of furafylline or ketoconazole.

Therefore, ARI-186, ARI-224, and ARI-226 are compounds that appear tohave selectively removed the CYP1A1/1A2-mediated oxidation of ARI-164,while preserving or improving potency.

Surprisingly, several chiral pairs appeared to demonstrate cleardifferences in terms of turnover and CYP metabolic liability. Forexample, ARI-223 was high turnover with CYP1A2 metabolic contributionwhile ARI-224 was not. Similarly, ARI-225 was high turnover with CYP1A2metabolic contribution while ARI-226 was not. Also, ARI-228 was highturnover with CYP1A2 metabolic contribution while ARI-229 was not.

Example 47: In vivo pharmacokinetic studies in mice and rats

This example describes pharmacokinetic (PK) studies of ARI-164, ARI-165,ARI-186, ARI-224, and ARI-226 in mice and rats. In the present studies,the test compounds were given to groups of mice and/or rats (N=3 in eachgroup), intravenously (IV) at 2 mg/kg or orally (PO) at 10, 30, or 40mg/kg. ARI-186, ARI-224 and ARI-226 were given orally to rats QD for 5days at 10 mg/kg to assess whether decreased susceptibility toCYP1A1/1A2 metabolism would lead to increased accumulation. IV doseswere formulated in DMSO, while PO doses were formulated in a 50/50mixture of PEG400 and Tween 80 (single dose mouse and rat studies forARI-64, ARI-165, ARI-186, ARI-224, ARI-226) or PEG400/KolliphorHS15/Oleic Acid 45/45/10 (AR-164 repeat dose rat study). Blood sampleswere collected at pre-dose and over a period of 24 hours post-dose.Plasma concentrations of the test compounds were determined by HPLC.

Results:

Tables 6a-h below show the results of PK studies on the select compoundsin rats and mice.

TABLE 6a Single Dose PK Studies in Rats Following a 2 mg/kg IV or 10mg/kg Oral Dose of ARI-164 ARI-164 PK Parameters AUCinf CI Vss DosedGroup_ Dosage Animal_ Tmax Cmax T1/2 MRTlast MRTinf AUClast (hr * (mL/(mL/ Compound ID Route (mg/kg) ID (hr) (ng/mL) (hr) (hr) (hr) (hr *ng/mL) ng/mL) hr/kg) kg) ARI-164 1 IV 2 1 0.083 44500 2.24 1.03 1.0421000 21000 95.1 98.6 2 0.083 42200 3.91 1.38 1.53 20300 20500 97.8 1493 0.083 35400 2.39 2.49 2.5 23000 23000 87.1 218 Mean 0.083 40700 2.851.63 1.69 21400 21500 93.3 155 SD 0 4730  0.926 0.76 0.744 1350 13105.56 59.7 CV % 0 11.6 32.5   46.5  44.1 6.3 6.11 5.95 38.5 AUCIastAUCinf Dosed Group_ Dosage Animal_ Tmax Cmax Tl/2 MRTIast MRTinf (hr *(hr * F Compound ID Route (mg/kg) ID (hr) (ng/mL) (hr) (hr) (hr) ng/mL)ng/mL) (%) ARI-164 2 PO 10 4 2 532 0.56 2.64 2.65 2110 2110 5 2 6460.746 3.02 3.05 2650 2660 6 1 354 2.82 2.88 2.92 1500 1500 Mean 1.67 5111.37 2.85 2.87 2090 2090 1.94 SD 0.577 147 1.25 0.19  0.203 574 578 CV %34.6 28.8 91.2 6.68 7.07 27.5 27.6 F %: Bioavailability

TABLE 6b Single Dose PK Studies in Rats Following a 2 mg/kg IV or 10mg/kg Oral Dose of ARI-165 ARI-165 PK Parameters AUClast AUCinf CI VssDosed Animal_ Tmax Cmax Tl/2 MRTIast MRTinf (hr * (hr * (mL/ (mL/Compound Group Route Dosage ID (hr) (ng/ml) (hr) (hr) (hr) ng/mL) ng/mL)hr/kg) kg) ARI-165 1 IV 2 1 0.083 3880 0.83 0.8 0.91 2620 2690 744 677 20.083 36500 1.07 0.79 0.81 19500 19500 103 83.2 3 0.083 17100 2.11 1.281.61 15700 16300 123 198 Mean 0.083 19200 1.33 0.959 1.11 12600 12800323 320 SD 0    16400 0.68 0.28 0.436 8840 8930 365 315 CV % 0    85.651.1 29.2 39.2 70.2 69.6 113 98.7 AUClast AUCinf Dosed Group_ DosageAnimal_ Tmax Cmax Tl/2 MRTIast MRTinf (hr * (hr * F Compound ID Route(mg/kg) ID (hr) (ng/ml) (hr) (hr) (hr) ng/mL) ng/mL) (%) ARI-165 2 PO 104 2 1250 1.87 2.71 3.41 4260 4680 5 2 1070 0.541 3.12 3.12 4640 4650 6 21040 0.87 2.64 2.71 3560 3620 Mean 2 1120 1.09 2.82 3.08 4160 4310 6.73SD 0 114 0.692 0.259 0.355 548 604 CV % 0 10.1 63.2 9.17 11.5 13.2 14 F%: Bioavailability

TABLE 6c Repeat Dose PK Studies in Rats Following a 30 mg/kg Oral Doseof ARI-164 C_(max)/Dose AUC_(0-24 hr) AUC_(0-24 hr)/Dose Dose C_(max)(kg * T_(max) ^(a) T_(max) ^(a) AUC_(Tlast) (hr * (hr * kg * Analyte(mg/kg) Day Gender Statistic (ng/mL) ng/mL/mg) (hr) (hr) (hr * ng/mL)ng/mL) ng/mL/mg) R^(b) R^(c) F:M^(d) ARI-164 30 1 Male N 5 5 5 5 5 5 5NA NA NA Mean 499 16.6 1 8 1430 1510 50.3 NA NA NA SD 445 14.8 (1-1)(8-8) 1120 1110 37.1 NA NA NA CV % 89.1 89.1 NA NA 78.5 73.7 73.7 NA NANA ARI-164 30 7 Male N 5 2 2 2 NA NA NA NA NA NA Mean 2.93 0.245 1 NA NANA NA NA NA NA SD 5.29 NA (1-1) (1-4) NA NA NA NA NA NA CV % 180 NA NANA NA NA NA NA NA NA

TABLE 6d Repeat Dose PK Studies in Rats Following a 10 mg/kg Oral Doseof ARI-186 Dosage Tmax Cmax T1/2 MRTlast MRTinf AUClast AUCinf CompoundDay Route (mg/kg) Animal_ID (hr) (ng/mL) (hr) (hr) (hr) (hr * ng/mL)(hr * ng/mL) ARI-186 1 PO 10 1 8 397 6.44 8.14 10.5 6260 6920 2 8 3596.45 8.40 10.9 5400 6000 3 4 441 5.22 7.63 8.93 6150 6510 Mean 6.67 3996.04 8.06 10.1 5940 6480 SD 2.31 41 0.71 0.395 1.04 469 461 CV % 34.610.3 11.8 4.9 10.3 7.89 7.11 ARI-186 5 PO 10 1 2 1610 NC 11.6 NC 33600NC 2 8 1310 NC 11.6 NC 24600 NC 3 4 1810 NC 11.4 NC 29100 NC Mean 4.671580 NC 11.5 NC 29100 NC SD 3.06 252 0.116 4480 CV % 65.5 16 1.01 15.4

TABLE 6e Single Dose PK Studies in Mice Following a 40 mg/kg Oral Doseof ARI-164 Time (hr) M1 M2 M3 Mean S.D. CV (%) 0.083 330 202 88 206.7 ±121 58.6 0.25 1780 1740 1350 1623 ± 238 14.6 0.5 1960 2020 1620 1867 ±216 11.6 1 1050 1600 930 1193 ± 357 29.9 2 463 572 482 506 ± 58 11.5 4101 79.3 68.2 82.8 ± 16.7 20.1 8 7.1 BLQ BLQ 7.1 ± NA NA 12 7.5 BLQ 5.66.5 ± 1.35 20.7 24 BLQ BLQ BLQ NA ± NA NA t_(1/2) (hr) 1.4 T_(max) (hr)0.5 C_(max) (ng/mL) 1867 AUC₀₋₄ 3008 (ng · hr/mL) AUC_(0-∞) 3021 (ng ·hr/mL) Bioavailability (%) 15.1%

TABLE 6f Single Dose PK Studies of ARI-186 in Mice MRT MRT AUClastAUCinf Cl Vss Group Dosage Tmax Cmax T1/2 last inf (hr * (hr * ng/(mL/hr/ (mL/ F* Compound ID Route (mg/kg) (hr) (ng/mL) (hr) (hr) (hr)ng/mL) mL) kg) kg) (%) ARI-186 1 IV 5 0.083 2130 7.62 6.99 9.55 1220013500 371 3550 ARI-186 2 PO 10 2 1380 5.56 6.76 8.21 16100 17000 63.0ARI-186 3 PO 40 2 5000 NC 9.35 NC 73900 NC 75.7** ARI-186 4 IP 40 0.56230 NC 11.2 NC 79400 NC 81.4**

TABLE 6g Repeat Dose PK Studies in Rats Following a 10 mg/kg Oral Doseof ARI-224 Dosage Tmax Cmax T1/2 MRTlast MRTinf AUClast AUCinf CompoundRoute (mg/kg) Day Animal_ID (hr) (ng/mL) (hr) (hr) (hr) (hr * ng/mL)(hr * ng/mL) ARI-224 PO 10 1 1 1 699 2.05 2.66 3.23 1990 2140 2 2 10901.04 2.42 2.48 4030 4070 3 1 587 1.57 2.36 2.66 1770 1840 Mean 1.33 7921.55 2.48 2.79 2600 2680 SD 0.577 264 0.507 0.159 0.389 1250 1210 CV %43.3 33.3 32.6 6.4 14 48.1 45.2 2 0.25 8.36 NA 8.95 NA 14.9 NA 3 0.253.98 1.28 1.44 1.95 7.28 8.24 Mean 0.333 5.96 1.28 4.56 1.95 11.4 8.24SD 0.144 2.22 NA 3.91 NA 3.84 NA CV % 43.3 37.3 NA 85.7 NA 33.7 NA

TABLE 6h Repeat Dose PK Studies in Rats Following a 10 mg/kg Oral Doseof ARI-226 Dosage Tmax Cmax T1/2 MRTlast MRTinf AUClast AUCinf CompoundRoute (mg/kg) Day Animal_lD (hr) (ng/mL) (hr) (hr) (hr) (hr * ng/mL)(hr * ng/mL) ARI-226 PO 10 1 4 4 188 2.55 5.18 5.23 1280 1280 5 4 28.42.39 5.96 5.99 253 253 6 4 119 1.89 6.21 6.22 963 963 Mean 4 112 2.285.78 5.81 831 832 SD 0 80 0.342 0.537 0.517 525 526 CV % 0 71.6 15.09.28 8.90 63.2 63.2 ARI-226 PO 10 5 4 1 5.33 1.05 1.56 1.89 13.0 14.2 52 13.2 1.87 2.76 3.31 50.9 54.7 6 2 10.8 2.01 3.15 3.82 43.2 47.3 Mean1.67 9.78 1.64 2.49 3.01 35.7 38.7 SD 0.577 4.03 0.519 0.831 1 20.0 21.5CV % 34.6 41.3 31.6 33.4 33.2 56.1 55.6

This study showed that surprisingly, after a single 40 mg/kg oral doseof AU-186, the AUC was 73,900 ng*hr/ml with 75.7% oral bioavailability(Table 6f). This is a major improvement over a single 40 mg/kg oral doseof ARI-164, which achieved only 3,008 ng*hr/ml with 15.1% oralbioavailability (Table 6e). This is a 24.6× improvement in AUC and a5.0× improvement in oral bioavailability. Half-lives for ARI-186 were inthe 7.6 hour range, significantly longer than ARI-164 half-life in miceof 1.4 hours.

It was also surprising that while ARI-164 showed a greater than 90%decrease in exposure after repeat oral dosing in rats at 30 mg/kg QD,ARI-186 saw a 4.9× accumulation, from 5,940 ng*hr/ml on day 1 to 29,100ng*hr/ml on day 5, thereby confirming the in vitro results with ARI-186and suggesting that ARI-186 was achieving steady-state pharmacokineticsafter 5 doses.

Furthermore, while ARI-186 showed accumulation towards steady stateafter 5 days of repeat dosing, surprisingly, ARI-224 and ARI-226 did not(Tables 6g and 6h). In fact, ARI-224 and ARI-226 showed increasedelimination after induction of CYP1A1/1A2. This suggests that althougheach of these compounds possess the same 6-fluoro indole moiety as wellas the same chiral amino group, the structural changes on the thiazoleend of the molecule contribute significantly to the CYP metabolicprofiles of these molecules.

Example 48: Anti-tumor activity of ARI-143, ARI-164 and ARI-165 inanimal models

This example describes in vivo studies that evaluated the anti-cancerefficacy of ARI-143, ARI-164, ARI-165, and ARI-186 in syngeneic mousetumor models. Mice implanted subcutaneously with EMT-6 or Pan02 cancercells were treated with ARI-143, ARI-164, ARI-165, ARI-186, or vehiclecontrols, as described below.

Materials and Methods Cell Culture

A monolayer culture of tumor cells was maintained in vitro in DMEM orRPMI1640 medium supplemented with 10% fetal bovine serum at 37° C. in anatmosphere of 5% CO₂. Cells in exponential growth phase were harvestedand quantitated by cell counter before tumor inoculation. The cell linesused are described in the table below.

Cell Line Cancer Type Culture Medium EMT-6 breast cancer DMEM + 10% FBSPan02 pancreatic cancer RPMI1640 + 10% FBS

Subcutaneous Syngeneic Mouse Tumor Models

Two subcutaneous syngeneic mouse tumor models were generated byinnoculating female BALB/C or C57BL/6 mice with cancer cells at theirright lower or front flank as detailed in the table below:

Cell line Cell Number Inoculation site MouseStrain EMT-6 5 × 10⁵ rightlower flank BALB/C Pan02 3 × 10⁶ right front flank C57BL/6

Each mouse was inoculated subcutaneously with tumor cells in 0.1 mL ofPBS. Treatments were started when the mean tumor size reachedapproximately 80-120 mm³ (around 100 mm³). The administration of thetest compounds and the animal number in each study group are shown inthe study design. The date of tumor cell inoculation was denoted as day0.

Formulation of Test Compounds

ARI-143, ARI-164, and ARI-165 were dissolved in DMSO at the finalconcentration of 26.7 mg/ml and stored at room temperature. In Pan02studies of ARI-164 and ARI-186, both compounds were dissolved in 100%PEG400.

Study Design

Randomization of animals was started when the mean tumor size reachedapproximately 90 mm³ to form the mouse study groups. The randomizationwas performed based on “Matched distribution” method using themulti-task method (StudyDirector™ software, version3.1.399.19)/randomized block design. The mouse groups (ten in eachgroup) were treated with vehicle (DMSO or PEG400) or the test compoundsat a dose of 20-80 mg/kg by intraperitoneal (i.p.). injection, QD for 28days or longer.

Observation and Data Collection

After tumor cell inoculation, the mice were checked daily for morbidityand mortality. During routine monitoring, the mice were checked fortumor growth and any effects of the treatment on behavior such asmobility, food and water consumption, body weight gain/loss (bodyweights were measured twice per week after randomization), eye/hairmatting, and any other abnormalities. Mortality and observed clinicalsigns were recorded for individual mice in detail.

Tumor volumes were measured twice per week in two dimensions using acaliper, and the volume was expressed in mm³ using the formula:

V=(L×W×W)/2,

where V is tumor volume, L is tumor length (the longest tumor dimension)and W is tumor width (the longest tumor dimension perpendicular to L).Dosing as well as tumor and body weight measurements was conducted in aLaminar Flow Cabinet. The body weights and tumor volumes were measuredby using StudyDirector™ software (version 3.1.399.19).

Dosing Holiday

A dosing holiday was given to the mice after one measurement of bodyweight loss (BWL) >30%. The length of the dosing holiday was long enoughfor the body weight to recover to BWL <30%, at which time the treatmentwas resumed. The mice were not fed any additional nutrient supplementduring the dosing holiday.

Experimental Termination

Tumor growth inhibition percentage (TGI %) is an indicator for antitumoractivity of a drug compound, and expressed as:

TGI(%)=100×(1−T/C),

where T and C are the mean tumor volume (or weight) of the treated andcontrol groups, respectively, on a given day. Statistical analysis ofthe difference in mean tumor volume (MTV) among the groups was conductedusing the data collected on the day when the MTV of the vehicle groupreached the humane endpoints, so that TGI could be derived for all ormost mice enrolled in the study.

The body weight of all animals was monitored throughout the study andanimals were euthanized if they lost over 20% of their body weightrelative to the weight at the start of the study and could not recoverwithin 72 hours.

All of the mice in the same group would be sacrificed when the MTVreached 2000 mm³, or an individual mouse would be sacrificed when thetumor volume reached 3000 mm³.

To deter cannibalization, any animal exhibiting an ulcerated or necrotictumor would be separated immediately and singly housed and monitoreddaily before the animal was euthanized or until tumor regression wascomplete. Mouse with tumor ulceration of approximately 25% or greater onthe surface of the tumor would be euthanized.

Statistical Analysis

For comparison between two groups, a Student's t-test was performed. Alldata were analyzed using SPSS 18.0 and/or GraphPad Prism 5.0. P<0.05 wasconsidered statistically significant.

Results

In vivo studies were performed in the above-described syngeneic mousetumor models to evaluate the anti-tumor activity of ARI-143, ARI-164,ARI-165, and ARI-186.

TABLE 7 TGI data—ARI-164 vs ARI-165 Study Days 6 10 13 17 20 24 27 31ARI-164, 40 mg/kg, IP 0.1% −10.8% −2.4% 20.8% 41.6% 54.7% 54.3% 56.2%ARI-165, 40 mg/kg, IP 0.0% −7.9% −8.6% 14.5% 23.1% 25.8% 12.5% 9.1%

TABLE 8 TGI data—ARI-143 vs ARI-164 vs ARI-165 Study Days 6 10 13 17 2024 27 31 ARI-164, 40 mg/kg, IP 0.1% −10.8% −2.4% 20.8% 41.6% 54.7% 54.3%56.2% ARI-165, 40 mg/kg, IP 0.0% −7.9% −8.6% 14.5% 23.1% 25.8% 12.5%9.1% ARI-143 (susp), 40 mg/kg, IP 0.1% −10.1% 0.6% 30.9% 41.0% 53.2%51.8% 54.8%

TABLE 9 TGI data—ARI-164 vs ARI-186 Study Days 0 4 7 11 14 18 ARI-164,−0.6% −4.4% −8.4% 26.6% 40.6% 35.3% 80 mg/kg, IP ARI-186, −2.0% −13.0%−0.3% 27.0% 49.5% 61.9% 20 mg/kg, IP

Surprisingly, ARI-186 was much more effective at suppressing Pan02tumors at 20 mpk than ARI-164 was at 80 mpk. At study day 18, ARI-186 20mpk resulted in 62% tumor inhibition versus vehicle as compared toARI-164 80 mpk which resulted in 35% tumor inhibition versus vehicle(FIG. 20C).

Example 49: In Vivo Anti-Tumor Activity of ARI-164 in Combination withan Anti-PD-1 Antibody

In this example, the in vivo anti-tumor efficacy of a combination ofARI-164 with an anti-PD-1 antibody was evaluated using a panel of sevensubcutaneous syngeneic mouse tumor models.

Materials and Methods Subcutaneous Syngeneic Mouse Tumor Models

Seven subcutaneous syngeneic mouse tumor models were generated byinnoculating female BALB/C or C57BL/6 mice with cancer cells at theirright lower or right front flank followed by randomization as detailedin Table 10 below.

TABLE 10 Age at Tumor Randomization Mouse Cell Cancer Cell InoculationInnoculation on Strain line Type Number site (weeks) Day BALB/C 4T-1Breast 3 × 10⁵ Breast orthotopic 7-9 8 BALB/C A20 Lymphoma 5 × 10⁵ rightlower flank 7-9 12 BALB/C EMT-6 Breast 5 × 10⁵ right lower flank 7-9 6C57BL/6 Pan02 Pancreatic 3 × 10⁶ right front flank 6-8 4 BALB/C H22Liver 1 × 10⁶ right front flank 6-8 5 C57BL/6 LL/2 Lung 3 × 10⁵ rightlower flank 7-9 16 C57BL/6 MC38 Colon 1 × 10⁶ right lower flank 7-9 9

Formulation of Anti-PD-1 Antibody, ARI-164

A solution of a rat monoclonal anti-mouse PD-1 antibody (isotypeIgG_(2a), κ) at a concentration of 6.61 mg/ml was obtained from BioXcell(InVivoMAb anti-mouse PD-1 (CD279), Clone RMP1-14, Cat #BE0146)) andstore at 4° C. The antibody solution was diluted with PBS to obtain a 1mg/ml dosing solution.

ARI-164 powder was stored at −20° C. The powder of the compound wasdissolved in DMSO to obtain dosing solutions at 26.7 mg/ml foradministration to mice at 40 mg/kg, respectively.

Study Design and Randomization

Seven studies using the seven subcutaneous syngeneic mouse tumor modelswere performed. In each study, 80 mice were enrolled and randomlyallocated to eight different study groups, with 10 mice in each studygroup. The mean tumor size at randomization was approximately 80-120 mm³(around 100 mm³). Randomization was performed based on “Matcheddistribution” randomization method (StudyDirector™ software, version3.1.399.19). Table 6 shows the study design and the actual dosingfrequency and number of doses. All the drugs and vehicle controls wereinjected to the mice intraperitoneally.

TABLE 11 Dose Dose Vol. Dose Freq. Group No. Treatment (mg/kg) (ml/kg) &Numbers Study 1—4T-1 1 Vehicle (DMSO) 0 10 QD × 23 doses 2 Anti-PD-1 1010 BIW × 7 doses 3 ARI-164 40 1.5 QD × 23 doses 4 Anti-PD-1 10 10 BIW ×7 doses ARI-164 40 1.5 QD × 21 doses Study 2—A20 1 Vehicle (DMSO) 0 10QD × 17 doses 2 Anti-PD-1 10 10 BIW × 6 doses 3 ARI-164 40 1.5 QD × 17doses 4 Anti-PD-1 10 10 BIW × 6 doses ARI-164 40 1.5 QD × 17 doses Study3—EMT-6 1 Vehicle (DMSO) 0 10 QD × 24 doses 2 Anti-PD-1 10 10 BIW × 8doses 3 ARI-164 40 1.5 QD × 24 doses 4 Anti-PD-1 10 10 BIW × 8 dosesARI-164 40 1.5 QD × 24 doses Study 4—Pan02 1 Vehicle (DMSO) 0 10 QD × 49doses 2 Anti-PD-1 10 10 BIW × 14 doses 3 ARI-164 40 1.5 QD × 49 doses 4Anti-PD-1 10 10 BIW × 14 doses ARI-164 40 1.5 QD × 49 doses Study 5—H221 Vehicle (DMSO) 0 10 QD × 18 doses 2 Anti-PD-1 10 10 BIW × 6 doses 3ARI-164 40 1.5 QD × 18 doses 4 Anti-PD-1 10 10 BIW × 6 doses ARI-164 401.5 QD × 18 doses Study 6—LL/2 1 Vehicle (DMSO) 0 10 QD × 20 doses 2Anti-PD-1 10 10 BIW × 6 doses 3 ARI-164 40 1.5 QD × 20 doses 4 Anti-PD-110 10 BIW × 6 doses ARI-164 40 1.5 QD × 20 doses Study 7—MC38 1 Vehicle(DMSO) 0 10 QD × 20 doses 2 Anti-PD-1 10 10 BIW × 4 doses 3 ARI-164 1601.5 QD × 20 doses 4 Anti-PD-1 10 10 BIW × 4 doses ARI-164 160 1.5 QD ×20 doses

The data was collected and analyzed as described above in Example 48.

Results Tumor Growth Inhibition

FIGS. 21A-G are graphs showing mean tumor volumes on different studydays in the study groups as indicated according to studies 1-7,respectively. The TGI data are summarized in Table 12.

TABLE 11 TGI in Tumor Models TGI (%) Group Treatment 4T-1 A20 EMT-6Pan02 H22 LL/2 MC38 1 Vehicle (PBS) — — — — — — — 2 Anti-PD-1 4.8 3.755.5 23.8 50.1 1.3 29.0 3 ARI-164 45.3 28.1 57.2 61.1 46.9 42.5 18.8 4Anti-PD-1 + 64.6 68.9 91.6 75.4 82.9 43.0 59.1 ARI-164

4T-1 is a very aggressive breast line that is resistant to anti-PD-1.Surprisingly, not only did ARI-164 delay tumor growth, thereby improvingsurvival curves, but its combination with an anti-PD-1 antibody resultedin a statistically significant delta in tumor growth inhibition at studyday 31 (FIG. 21A).

Combination of ARI-164 with an anti-PD-1 antibody led to significanttumor inhibition at study day 28 in the A20 model (FIG. 21B).

Combination of ARI-164 with an anti-PD-1 antibody led to significanttumor inhibition at study day 30 in the EMT-6 model (FIG. 21C).

Combination of ARI-164 with an anti-PD-1 antibody led to increased tumorinhibition at study day 55 in Pan02, though given Pan02 is almostcompletely insensitive to anti-PD-1, the vast majority of this activitywas likely due to ARI-164 (FIG. 21D).

Combination of ARI-164 with an anti-PD-1 antibody led to significanttumor inhibition at study day 24 in the H22 model (FIG. 21E).

Combination of ARI-164 with an anti-PD-1 antibody led to tumorinhibition at study day 32, but the vast majority of this activity waslikely due to ARI-164 (FIG. 21F).

Combination of ARI-164 with an anti-PD-1 antibody led to significanttumor inhibition at study day 27 in the MC38 model (FIG. 21G).

1-27. (canceled)
 28. A method of stimulating or modulating the immunesystem in a patient in need thereof, comprising administering to thepatient a therapeutically effective amount of a compound of StructuralFormula 8c or Structural Formula 8d, or a pharmaceutically acceptablesalt thereof,

wherein R₄, R₅, R₆, and R₇, are each, independently, selected from thegroup consisting of hydrogen and halo; R_(o) is hydrogen, deuterium,alkyl, aryl, or acyl; and R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl,alkanoyl, carbonyloxy, carbonylthio, carbonylamino, or a phosphatemoiety.
 29. The method of claim 28, wherein R_(o) is H, alkyl, or acyl.30. (canceled)
 31. The method of claim 28, wherein R_(o) is substitutedor unsubstituted C₁-C₆ acyl, wherein the substituted or unsubstitutedC₁-C₆ acyl can be a substituted C₂, C₃, C₄, C₅, or C₆ acyl, optionallyinterrupted by O, S, or NR (in which NR can be N-C1-C6 alkyl), whereinthe substituent is a halo, carboxyl, amino, hydroxyl, alkoxy, orphosphonate moiety.
 32. The method of claim 28, wherein at least one ofR₄, R₅, R₆, and R₇ is F, Cl, or Br, and the others of R₄, R₅, R₆, and R₇are hydrogen.
 33. (canceled)
 34. The method of claim 28, wherein R₅ is For Cl, and R₄, R₆, and R₇ are hydrogen.
 35. The method of claim 28,wherein R₆ is F or Cl, and R₄, R₅, and R₇ are hydrogen.
 36. The methodof claim 28, wherein R₇ is F or Cl, and R₄, R₅, and R₆ are hydrogen.37-39. (canceled)
 40. The method of claim 28, wherein R₅ and R₆ are F orCl, and R₄ and R₇ are hydrogen.
 41. The method of claim 28, wherein R₅and R₇ are F or Cl, and R₄ and R₆ are hydrogen.
 42. The method of claim28, wherein R₆ and R₇ are F or Cl, and R₄ and R₅ are hydrogen. 43-45.(canceled)
 46. The method of claim 28, wherein each of R₄, R₅, R₆, andR₇ is hydrogen.
 47. The method of claim 28, wherein R_(N) is a phosphatemoiety. 48-62. (canceled)
 63. The method of claim 28, wherein thecompound gf Structural Formula 8d has the structure

or is a pharmaceutically acceptable salt thereof.
 64. The method ofclaim 28, wherein the compound gf Structural Formula 8c has thestructure

or is a pharmaceutically acceptable salt thereof.
 65. (canceled)
 66. Themethod of claim 28, wherein the compound is administered as apharmaceutical composition comprising the compound and apharmaceutically acceptable carrier.
 67. (canceled)
 68. The method ofclaim 28, wherein the compound decreases IL-21 level in the patient. 69.The method of claim 68, wherein the patient has cancer.
 70. A method oftreating cancer in a patient in need thereof, comprising administeringto the patient a therapeutically effective amount of a compound ofStructural Formula 8c or Structural Formula 8d, or a pharmaceuticallyacceptable salt thereof,

wherein R₄, R₅, R₆, and R₇, are each, independently, selected from thegroup consisting of hydrogen and halo; R_(o) is hydrogen, deuterium,alkyl, aryl, or acyl; and R_(N) is H, CN, alkyl, alkenyl, alkynyl, aryl,alkanoyl, carbonyloxy, carbonylthio, carbonylamino, or a phosphatemoiety.
 71. The method of claim 70, wherein the cancer is selected fromthe group consisting of lymphoma, leukemia, myeloma, prostate cancer,lung cancer, ovarian cancer, cervical cancer, breast cancer, skincancer, colorectal cancer, stomach cancer, pancreatic cancer, livercancer, kidney cancer, bladder cancer, soft tissue cancer, glioma, andhead and neck cancer.
 72. The method of claim 70, further comprisingadministering to the patient another cancer therapeutic agent. 73-74.(canceled)
 75. A method of making a compound of Structural Formula 9, oran enantiomer, diastereomer, or pharmaceutically acceptable saltthereof:

wherein: Z₁ is N or CR₄, Z₂ is N or CR₅, Z₃ is N or CR₆, Z₄ is N or CR₇,Z₅ is N or CR₈, Z₆ is N or C, Z₇ is N or C, wherein no more than two ofZ₁, Z₂, Z₃, Z₄, Z₅, Z₆, and Z₇ are N; R₄, R₅, R₆, R₇, R₈, and R₉ areeach independently selected from the group consisting of hydrogen,deuterium, halo, amino, hydroxy, cyano, formyl, furyl, nitro, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, halothiocarbonylthio, and —S(O)_(n)R₁₁ (n=0 to 2, R₁₁is directly connected to S), wherein R₁₁ is selected from the groupconsisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano,formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl,haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy,halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy,halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio; R₃ isselected from the group consisting of deuterium, cyano, formyl, furyl,nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,C₁-C₆ acyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy,alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy,carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio,thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio,halothiocarbonylthio, and —S(O)_(n)R₁₀ (n=0 to 2, R₁₀ is directlyconnected to S), wherein R₁₀ is selected from the group consisting ofhydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy,haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl,thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy,carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy,thiocarbonylthio, and halothiocarbonylthio; R_(3a) is selected from thegroup consisting of hydrogen, deuterium, cyano, or C₁-C₆ alkyl; R_(o) ishydrogen, deuterium, alkyl, aryl, or acyl; each R_(N) is H, CN, alkyl,alkenyl, alkynyl, aryl, alkanoyl, carbonyloxy, carbonylthio,carbonylamino, or a phosphate moiety; and optionally, adjacent R groups,together, can form a three- to twelve-membered ring; comprising: (i)contacting a compound of Structural Formula 10 with(S)-2-methylpropane-2-sulfinamide in the presence of a catalyst to yielda compound of Structural Formula 11;

(ii) contacting a compound of Structural Formula 11 with one or morealkylating agent(s) to yield a compound of Structural Formula 12;

(iii) contacting a compound of Structural Formula 12 with a compound ofStructural Formula 13 in the presence of an organolithium base to yielda compound of Structural Formula 14;

(iv) subjecting a compound of Structural Formula 14 to acid-basehydrolysis to obtain a compound of Structural Formula
 9. 76-84.(canceled)